ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.470T>C (p.Ile157Thr) (rs17879961)

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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212410 SCV000149927 likely pathogenic not provided 2019-09-30 criteria provided, single submitter clinical testing Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid cancers, though some odds ratios are only modestly elevated (Seppala 2003; Cybulski 2004; Kilpivaara 2006; Suchy 2010; Desrichard 2011; Liu 2012; Roeb 2012; Han 2013; Teodorczyk 2013; Kaczmarek-Rys 2015; Siolek 2015; Carlo 2018) Published functional studies demonstrate a damaging effect with respect to autophosphorylation, binding of downstream targets, and DNA damage response, and may exhibit a dominant-negative effect, while studies assessing kinase activity have varied results (Falck 2001a; Falck 2001b; Lee 2001; Wu 2001; Li 2002; Schwarz 2003; Kilpivaara 2004; Roeb 2012) Observed in 0.5% (1,403/277,192) of global alleles in large population cohorts, and is considered a founder variant with a frequency of up to 5.3% and 4.8%, respectively, in Finnish and Polish individuals (Desrichard 2011; Lek 2016) Located in a critical functional domain: forkhead-associated (FHA) domain (Cai 2009; Roeb 2012) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV000116018 SCV000183804 pathogenic Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing The p.I157T pathogenic mutation (also known as c.470T>C) is located in coding exon 3 of the CHEK2 gene. This mutation results from a T to C substitution at nucleotide position 470. The isoleucine at codon 157 is replaced by threonine, an amino acid with similar properties. Several large case-control studies and meta-analyses have estimated a 1.5-fold increased risk of breast cancer (4-fold risk for lobular breast cancer), up to a 2-fold increased risk of colorectal cancer, and an increased risk for prostate cancer and thyroid cancer (precise risk unknown) associated with the p.I157T mutation (Zhang B et al. Lancet Oncol. 2011 May;12:477-88; Liu C et al. Asian Pac. J. Cancer Prev. 2012;13:1355-60; Han FF et al. DNA Cell Biol. 2013 Jun;32:329-35; Liu C et al. Asian Pac. J. Cancer Prev. 2012;13:2051-5; Cybulski C et al. Cancer Res. 2004 Apr;64:2677-9; Kaczmarek-Ryś M et al. Hered Cancer Clin Pract. 2015 Mar;13:8; Siołek M et al. Int. J. Cancer. 2015 Aug;137:548-52). This alteration is located in the FHA protein domain and although there are some conflicting functional studies (Wu X et al. J. Biol. Chem. 2001 Jan;276:2971-4; Schwarz JK et al. Mol. Cancer Res. 2003 Jun;1:598-609; Lee SB et al. Cancer Res. 2001 Nov;61:8062-7; Lee CH and Chung JH. J. Biol. Chem. 2001 Aug;276:30537-41; Ahn JY et al. J. Biol. Chem. 2002 May;277:19389-95; Kilpivaara O et al. Int. J. Cancer. 2004 Sep;111:543-7; Cai Z et al. Mol. Cell. 2009 Sep;35:818-2), the majority agree that this alteration confers impaired phosphoprotein binding and kinase activities on some CHK2 substrates, which could contribute to defective DNA damage repair and delay the cell cycle checkpoint mechanism (Falck J et al. Nature. 2001 Apr;410:842-7; Falck J et al. Oncogene. 2001 Sep;20:5503-10; Li J et al. Mol. Cell. 2002 May;9:1045-54; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). Incomplete segregation of p.I157T with disease has been reported in familial breast cancer kindreds and has also been observed at high frequencies in general population databases, consistent with previous observations of intermediate cancer risk and reduced penetrance (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). This amino acid position is well conserved on sequence alignment in available species. The in silico prediction for this alteration is inconclusive and Roeb et al. speculate that fewer alignable sequences in the FHA domain may limit the predictive value of in silico models for alterations in this region (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). The available functional and epidemiological data support p.I157T as a pathogenic mutation; however, risks associated with this allele appear to be lower than those conferred by other CHEK2 mutations such as c.1100delC. As such, p.I157T is classified as a pathogenic mutation with moderate risk.
Invitae RCV000144596 SCV000253984 pathogenic Familial cancer of breast 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 157 of the CHEK2 protein (p.Ile157Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs17879961, ExAC 2.6%). This variant has been reported in the literature in large meta-analyses involving several thousand cases and controls. Individuals who carried the Ile157Thr variant had a slightly increased risk of breast cancer (OR=1.48-1.58) (PMID: 22799331, 23713947), and colorectal cancer (OR=1.48-1.67) (PMID: 22901170, 23713947). The risk was found to be more pronounced for lobular type breast tumors (OR=4.17) (PMID: 22799331). In addition, smaller case-control studies suggest this variant may also lead to increased risk of additional cancers, including kidney, prostate, thyroid, and gastric cancer (PMID: 15492928, 23296741, 24599715). ClinVar contains an entry for this variant (Variation ID: 5591). Experimental studies find that this missense change reduces the binding of the CHEK2 protein to Cdc25A, BRCA1 and p53 proteins in vitro and may have a dominant-negative effect in cells, although it does not have an effect on CHEK2 protein kinase activity (PMID: 11298456, 11571648, 15239132, 12049740, 22419737). The relationship between these experimental findings and cancer risk is unclear. In summary, this variant is reported to cause an increased risk for cancer. However, since this variant is associated with a much lower risk than other Pathogenic alleles in the CHEK2 gene, it has been classified as Pathogenic (low penetrance).
University of Washington Department of Laboratory Medicine, University of Washington RCV000210131 SCV000266064 likely pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000116018 SCV000292120 pathogenic Hereditary cancer-predisposing syndrome 2020-11-30 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000210131 SCV000296968 likely pathogenic Breast and colorectal cancer, susceptibility to 2018-05-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212410 SCV000575329 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000499814 SCV000594119 risk factor Breast cancer, susceptibility to 2019-12-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212410 SCV000601169 pathogenic not provided 2017-02-17 criteria provided, single submitter clinical testing
Counsyl RCV000144596 SCV000677722 likely pathogenic Familial cancer of breast 2016-03-15 criteria provided, single submitter clinical testing I157T has a reduced penetrance compared to the pathogenic CHEK2 mutation, c.1100delC.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120555 SCV000698803 uncertain significance not specified 2021-07-07 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.470T>C (p.Ile157Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain that is a phosphopeptide recognition domain (IPR000253). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was found at a frequency of 0.0042 in 253524 control chromosomes, including 11 homozygotes (gnomAD exomes dataset, and publications). This frequency is approximately 13.6-fold higher than the maximum expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.00031), suggesting that the variant is a benign polymorphism. In certain subpopulations the variant was found with even higher frequencies, e.g. within the Finnish (2.5%, gnomAD), Estonian (4.6%, gnomAD) and Polish (4-6%; e.g. Cybulski_2004, Lukomska_2021). The variant has also been reported in 47/7325 European American women (including 1 homozygote), who are older than age 70 and cancer free (FLOSSIES database). However, c.470T>C has been reported in the literature in several individuals affected with breast- and/or ovarian cancer. In families with this variant, transmissions of the variant allele, as well as the reference allele to affected individuals were reported, in addition to unaffected individuals who harbored the variant (e.g. Allinen_2001, Dong_2003, Roeb_2012, Bak_2014, Cragun_2014, Stradella_2018). These data indicate that the variant is likely to be associated with disease, but also suggests incomplete segregation and low penetrance. Co-occurrences with other pathogenic variants have been reported in CHEK2, as well as in other genes associated with cancer (e.g. BRCA2 c.6468_6469delTC [p.Gln2157fsX18]; NBN c.657_661delACAAA [p.Lys219fsX16]; BRCA1 c.3700_3704delGTAAA [p.Val1234fsX8]; CHEK2 c.444+1G>A; CHEK2 1100delC [p.Thr367fsX15]; CHEK2 c.433C>T [p.Arg145Trp]), providing supporting evidence for a benign role, though in some of these cases the observed phenotype (earlier onset), could also suggest an additive effect (Stradella_2018). Multiple association studies have produced conflicting results, with an overall consensus for the variant being associated with a moderate risk for breast cancer, based on a large meta-analysis by Liu_2012 that included a total of fifteen case-control studies (19,621 cases and 27,001 controls), showing a significant association for (unselected) breast cancer (OR = 1.48, 95% CI = 1.31-1.66, P < 0.0001). Another study indicated a lack of risk association with ovarian cancer (Lukomska_2021), and a large study found no statistically significant difference in overall- or breast cancer-specific survival between carriers of this variant and non-carriers (Muranen_2016). Multiple functional studies reported experimental evidence evaluating an impact on protein function, and demonstrated retained kinase activity (Lee_2001, Chrisanthar_2008), decreased interaction with p53 and BRCA1 (Falck_2001, Li_2002, Bazinet_2021) and impaired CHEK2 oligomerization with reduced autophosphorylation (Schwarz_2003). A recent study assigned a "benign" functional classification to the variant based on its DNA repair-ability after chemically induced DNA damage (Delimitsou_2019), while another study classified it as an "intermediate" function variant with decreased catalytic activity (Kleiblova_2019). Twentyone other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=6) / likely pathogenic (n=10), VUS (n=4) or risk factor (n=1), acknowledging the low penetrance and risk association. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, due to the probability of this variant for being a possible moderate risk factor for HBOC.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626718 SCV000747421 uncertain significance Gastrointestinal carcinoma; Adrenocortical carcinoma 2017-01-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212410 SCV000806880 likely pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116018 SCV000821722 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 157 of the CHEK2 protein (p.Ile157Thr). The isoleucine residue is moderately conserved and there is a moderate physiochemical difference between isoleucine and threonine.This variant is present in population databases (rs17879961, 2.6%) and has been reported in the literature. ClinVar contains entries for this variant (RC000116018, RC000144596).In large meta-analyses involving several thousand cases and controls, patients who carried this variant had a slightly increased risk of breast cancer (OR=1.48-1.58) (PMID: 22799331, 23713947), and colorectal cancer (OR=1.48-1.67) (PMID: 22901170, 23713947). The risk was found to be more pronounced for lobular breast tumors (OR=4.17) (PMID: 22799331).Smaller case-control studies suggest this variant may also lead to increased risk of additional cancers, including kidney, prostate, thyroid, and gastric cancer (PMID: 15492928, 23296741, 24599715).Experimental studies find that this missense change reduces the binding of the CHEK2 protein to Cdc25A, BRCA1 and p53 proteins in vitro and may have a dominant-negative effect in cells, although it does not have an effect on CHEK2 protein kinase activity (PMID: 11298456, 11571648, 15239132, 12049740, 22419737). The relationship between these experimental findings and the cancer risk is unclear. In summary, this variant is reported to cause an increased risk for cancer, however, since this variant is associated with a much lower risk than other Pathogenic alleles in the CHEK2 gene, it has been classified as Likely Pathogenic (low penetrance).
Mendelics RCV000144596 SCV000839491 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000144596 SCV000839939 pathogenic Familial cancer of breast 2017-06-02 criteria provided, single submitter clinical testing This c.470T>C (p.Ile157Thr) variant in the CHEK2 gene has been reported to be associated with cancer susceptibility, including significant association with increased risk of breast and colon cancer in large meta-analysis studies [odds ratios ~1.5, PMID: 22901170, 22799331, 23713947]. Co-segregation in families is variable: while families have been reported with complete penetrance, others show incomplete penetrance [PMID 22419737]. In vitro and in vivo studies have shown that the mutant allele does not affect the kinase activity of the protein [PMID 11719428] but does affect the dimerization of the protein in a dominant negative manner, resulting in the lack of autophosphosphorylation [PMID 12805407]. The mutant protein also impaired the binding of CHEK2 to check point proteins including CDC25A in response to DNA damage [PMID 11298456]. This variant was reported in 497 heterozygous and 6 homozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/22-29121087-A-G). Isoleucine at amino acid position 157 of the CHEK2 protein is conserved in mammals. While not validated for clinical use, computer-based algorithms (SIFT and Polyphen-2) predict this p.Ile157Thr change to be deleterious. It is thus classified as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282409 SCV001159433 likely pathogenic none provided 2019-10-11 criteria provided, single submitter clinical testing The CHEK2 c.470T>C; p.Ile157Thr variant (rs17879961) is reported in the medical literature in large case-controlled meta-analyses as associated with a slightly increased risk of breast cancer, colon cancer, kidney cancer, prostate cancer, thyroid cancer, and gastric cancer (Cybulski 2004, Han 2013, Teodorczyk 2013). In vitro assays suggest the variant protein has wildtype kinase activity but fails to interact with normal binding partners (Falck 2001, Li 2002, Wu 2001). The p.Ile157Thr variant is listed as pathogenic/likely pathogenic by numerous laboratories in ClinVar (Variation ID: 5591), though it is found in the general population with an overall allele frequency of 0.5% (1391/282816 alleles) in the Genome Aggregation Database. Due to the small but statistically significant increased risk of cancer, this variant is classified as a low penetrance likely pathogenic variant. References: Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 Dec;75(6):1131-5. Falck J et al. Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene. 2001 Sep 6;20(39):5503-10. Han FF et al. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 2013 Jun;32(6):329-35. Li J et al. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol Cell. 2002 May;9(5):1045-54. Teodorczyk U et al. The risk of gastric cancer in carriers of CHEK2 mutations. Fam Cancer. 2013 Sep;12(3):473-8. Wu X et al. Characterization of tumor-associated Chk2 mutations. J Biol Chem. 2001 Jan 26;276(4):2971-4.
Institute of Human Genetics, University of Leipzig Medical Center RCV000144596 SCV001429096 uncertain significance Familial cancer of breast 2018-02-26 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000116018 SCV001448804 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000116018 SCV001482296 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
OMIM RCV000005936 SCV000026118 pathogenic Li-Fraumeni syndrome 2 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005937 SCV000026119 risk factor Colorectal cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005938 SCV000026120 risk factor Cancer of multiple types, susceptibility to 2006-11-01 no assertion criteria provided literature only
OMIM RCV000005939 SCV000026121 risk factor Prostate cancer, susceptibility to 2006-11-01 no assertion criteria provided literature only
ITMI RCV000120555 SCV000084709 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144596 SCV000189923 likely pathogenic Familial cancer of breast 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000212410 SCV000691835 pathogenic not provided no assertion criteria provided clinical testing
True Health Diagnostics RCV000116018 SCV000788004 pathogenic Hereditary cancer-predisposing syndrome 2017-11-16 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000844971 SCV000986797 not provided Breast cancer, susceptibility to; Colon cancer, susceptibility to no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 05/09/2018 by GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Center of Medical Genetics and Primary Health Care RCV000144596 SCV000987254 likely pathogenic Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The CHEK2 variant p.Ile157Thr was observed in the kinase domain in a tight region between amino acid 407-499 and in a mutation hotspot of 13 pathogenic variants (PM1 Pathogenic Moderate). 4 functional studies (PMID: 12049740, 15239132, 11298456, & 11571648) confirmed the likely pathogenic effect of this variant (PS3 Pathogenic Strong). An alternative variant (chr22:29121087 A>C (Ile157Ser)) at the same amino acid residue is classified as likely pathogenic (PM5 Pathogenic Moderate). Meantime, majority of missense variants detected in CHEK2 are pathogenic and known cause of disease (PP2 Pathogenic Supporting). The homozygous allele count in GnomAD exomes is 11 which is greater the threshold 3 for dominant and recessive gene CHEK2 (BS2 Benign Strong). In our study the variant p.Ile157Thr was found in a 46-year-old female with family history of cancer. In summary, based on the evidence and given the previous reports of the variant in association with increased risk of breast cancer, we classified this variant as a Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358111 SCV001553764 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Ile157Thr variant was identified in 643 of 21182 proband chromosomes (frequency: 0.03) from individuals or families with breast, colorectal, ovarian, thyroid, endometrial, prostate, and pancreatic cancer, and was present in 815 of 34689 control chromosomes (frequency 0.02) from healthy individuals (Cybulsk 2006, Kilpivaara 2004, Kilpivaara 2006, Leedom 2016, Serrano-Fernandez 2008, Konstantinova 2009, Kuusisto 2011, Kleibl 2009, Lener 2016). The variant was also identified in dbSNP (rs17879961) as “With Likely pathogenic, Pathogenic allele”, ClinVar (classified as pathogenic by Ambry Genetics, Invitae, Color Genomics; classified as likely pathogenic by GeneDx, UWDLM; classified as uncertain significance by CHP, PHT), Cosmic (classified as pathogenic), MutDB, and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 1403 of 277192 chromosomes at a frequency of 0.005 in the following populations: European Finnish in 649 of 25786 chromosomes (freq. 0.03, 10 homozygotes), European non-Finnish in 685 of 126686 chromosomes (freq. 0.005, 7 homozygotes), population described as “other” in 52 of 6468 chromosomes (freq. 0.008, 1 homozygote), Ashkenazi Jewish in 12 of 10150 chromosomes (freq. 0.001), African in 2 of 24034 chromosomes (freq. 0.00008), Latino in 2 of 34420 chromosomes (freq. 0.00006), and South Asian in 1 of 30782 chromosomes (freq. 0.00003) (Genome Aggregation Consortium Feb 27, 2017). The p.Ile157Thr variant has been extensively described in the literature, however interpretation of these findings frequently conflict. It has been described as a founder mutation in the Polish population with a moderate risk association with breast cancer (including lobular breast cancer), colon, prostate, kidney, thyroid, bladder, endometrial, and low-grade ovarian cancers (Cybulsk 2006, Leedom 2016, Muranen 2016, Abud 2012). One study found a significant allelic association with chronic lymphoblastic leukemia (Rudd 2006). In addition, the variant which has been reported in ethnically diverse, high-risk families, and may represent both a founder mutation in some ethnic groups, but also may be a mutational hotspot (Kaufman, 2009). Two population studies found that the p.Ile157Thr variant was not found to be associated with cancer in the Iranian population (Jalilvand 2006) and the Turkish population (Bayram 2012). Liu et al (2012) performed a large meta-analysis of the p.Ile157Thr variant. They reviewed 15 studies including 19,621 cases and 27,001 controls. They found the p.Ile157Thr variant increases the risk of breast cancer about 1.5-fold. Another study reported the breast cancer risk associated with the variant to be 2-fold (Roeb 2011). A study of mutations in high-risk Finnish individuals with breast and/or ovarian cancer found this mutation co-occurring with the pathogenic CHEK2 c.1100delC mutation in one individual (Kuusisto 2011). This variant was observed by our laboratory in an individual with a co-occurring pathogenic variant in PALB2 (c.424A>T, p.Lys142X) and related to the reason for referral (breast cancer) increasing the likelihood this variant does not have clinical significance. The p.Ile157Thr residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Forkhead-associated (FHA) functional domain of the CHEK2 protein and has been shown to be defective in its ability to bind p53 and BRCA1 (Cybulsk 2006, Han 2013, Nevanlinna 2006, Schwarz 2003) however, another study (Falk 2001) showed that although the p.Ile157Thr variant showed lack of binding to p53, it was able to undergo the activatory mobility shift upon exposure to ionizing radiation. In addition, this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2 (Kilpivaara, 2004). The challenge of interpreting these data has been highlighted by two papers (Mundt 2017 28981386, Balmana 2016). Conflicting interpretation of functional data as well as interpretation of the variant’s relatively high allele frequency in control databases are thought to reflect the challenges of describing a so-called low-penetrance susceptibility allele in a format designed for high-penetrance alleles and rather than being universally low-penetrance, variants in this category may be associated with an increased risk for a subset of individuals, especially for those with a personal or family history of early-onset breast cancer (Byrnes 2008 18557994). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network RCV001535774 SCV001749921 not provided CHEK2-Related Cancer Susceptibility no assertion provided phenotyping only Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 12/10/20 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV000144596 SCV001774801 likely pathogenic Familial cancer of breast 2021-08-07 no assertion criteria provided clinical testing

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