Submissions for variant NM_007194.4(CHEK2):c.190G>A (p.Glu64Lys)

gnomAD frequency: 0.00015  dbSNP: rs141568342

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212407	SCV000149918	likely pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Published functional studies support a damaging effect: most show impaired phosphorylation, kinase activity, and DNA damage response (Wu et al., 2006; Roeb et al., 2012; Delimitsou et al., 2019; Kleiblova et al., 2019); Observed in individuals with CHEK2-related and other cancers (Dong et al., 2003; Wu et al., 2006; Desrichard et al., 2011; Roeb et al., 2012; Shirts et al., 2016; Tung et al., 2016; Kraus et al., 2017; Mandelker et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 27616075, 28135145, 29522266, 27779110, 27433846, 31786208, 16835864, 22419737, 30851065, 31050813, 12533788, 22114986, 26845104, 26976419, 28873162, 11733767, 33919281, 35053600, 32906215, 24082139, 16941491, 27067391, 26506619, 27696107, 28135136, 27621404, 28726808, 29555771, 29555025, 10973490, 31220302, 30322717, 31159747, 30303537, 30374176, 31101557, 32805687, 31980526, 32708810, 34426522, 34903604, 33606978, 32522261, 32923877, 35101071)
Ambry Genetics	RCV000116009	SCV000185901	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies conducted in multiple model systems have conflicting results as to the effect this protein has on substrate phosphorylation and DNA damage response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer. 2019 10;145:1782-1797; Boonen RACM et al. Cancer Res. 2022 Feb;82(4):615-631). Although this variant may segregate incompletely with disease, due to high false positive rates and low true positive rates with few pedigrees, co-segregation analysis should be used with extreme caution for genes with low relative risk like CHEK2 (Belman S et al. Genet. Med. 2020 Dec;22:2052-2059). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000199067	SCV000254934	likely pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein (p.Glu64Lys). This variant is present in population databases (rs141568342, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 12533788, 22114986, 24082139, 26681312, 26845104, 27616075, 27779110, 28135145; Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210191	SCV000266168	likely pathogenic	Breast and colorectal cancer, susceptibility to	2019-09-09	criteria provided, single submitter	clinical testing	This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study.
Counsyl	RCV000199067	SCV000488777	uncertain significance	Familial cancer of breast	2016-06-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212407	SCV000601160	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), breast cancer and or ovarian cancer (PMID: 22419737 (2012), 25186627 (2015), 26976419 (2016), 26681312 (2016), 26845104 (2016), 27616075 (2016), 27779110 (2017), 28779002 (2017), 29555771 (2018), 30322717 (2018), 30303537 (2019), 31050813 (2019), 32923877 (2020), 31786208 (2020), 32805687 (2020), 33919281 (2021), 33471991 (2021)) and colorectal cancer (PMID: 28135145 (2017)). The variant has also been reported in healthy individuals (PMID: 26506619 (2015), 28779002 (2017), 30303537 (2019), 33471991 (2021)). Functional studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function (PMID: 16835864 (2006), 22419737 (2012), 30851065 (2019)). The frequency of this variant in the general population, 0.00031 (16/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003389697	SCV000806876	uncertain significance	CHEK2-related condition	2024-01-12	criteria provided, single submitter	clinical testing	The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or family history of prostate or breast cancer (Dong et al. 2003. PubMed ID: 12533788; Wu et al. 2006. PubMed ID: 16835864; Desrichard et al. 2011. PubMed ID: 22114986; Kraus et al. 2016. PubMed ID: 27616075, Table S4). Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864). However, studies using a yeast functional assay to assess DNA damage response suggests this variant may be benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant has been observed in up to 0.03% of individuals in a subpopulation in the gnomAD database. This variant has also been observed in a person without cancer in a study involving individuals with non-Hodgkin lymphoma (Havranek et al. 2015. PubMed ID: 26506619). In ClinVar, it is listed as likely pathogenic and a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128068/). An internal summary of amino acid substitution prediction programs gives conflicting predictions for the p.Glu64Lys change (Liu et al. 2016. PMID: 26555599). We suspect this variant could be pathogenic; however, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneKor MSA	RCV000116009	SCV000821997	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000199067	SCV000839503	likely pathogenic	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212407	SCV000892320	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	CHEK2: PS4, PS3:Moderate, BS2
Color Diagnostics, LLC DBA Color Health	RCV000116009	SCV000902646	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 64 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604). One study has shown normal growth of yeast cells expressing the mutant protein following induction of DNA damage (PMID, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501, 26681312, 26845104, 26976419, 27616075, 31050813, 33919281, 36011273, 36315097), colorectal cancer (PMID: 26681312, 27696107, 28135145), ovarian cancer (PMID: 26681312, 27779110), pancreatic cancer (PMID: 26845104), prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), and sarcoma (PMID: 35053600). In one study, breast cancer prevalence in women who carry this variant does not show statistically significant difference when compared to women who carry CHEK2 c.1100delC variant (PMID: 32805687). However, this variant has also been reported in two large breast cancer case-control meta-analyses, in 66/60466 cases and 33/53461 unaffected controls; OR=1.769 (95%CI 1.165 to 2.687); (Leiden Open Variation Database DB-ID CHEK2_000075) (PMID: 33471991), and 72/73048 cases and 29/88658 unaffected controls OR=3.0153 (95%CI 1.9592 to 4.6408); (PMID: 37449874). This variant has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, its elevated frequency in the population and observations in unaffected individuals suggests that this variant may show reduced penetrance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265610	SCV000917231	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251468 control chromosomes, predominantly at a frequency of 0.0003 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (0.00031), suggesting that it could be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously, allowing no conclusion about variant significance.c.190G>A has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (examples: Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Carter_2018, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, and Dorling 2021) without evidence for causality, but also in controls (examples: Girard_2019, Kleiblova_2019, and Dorling 2021). However, in at least one family study, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals were reported, thus the variant did not co-segregate with disease (Kleiblova_2019). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The variant has also been reported in individuals with other cancer phenotypes, including colorectal cancer (examples- Susswein_2015, Rohlin_2016, Yurgelun_2017), prostate cancer (examples-Dong_2003, Wu_2006, Pritchard_2016, Abida_2017), and hereditary pancreatic cancer (example- Chaffee_2018). Several publications report experimental evidence evaluating an impact on protein function. Assays performed in yeast model systems have reported conflicting results: one study found that the variant impaired growth following DNA damage (Roeb_2012), while a similar study reported no significant impact on growth (Delimitsou_2019). Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 12533788, 26681312, 16835864, 26845104, 22114986, 27621404, 27616075, 27433846, 27696107, 28135145, 28726808, 30851065, 30374176, 30447919, 30322717, 30303537, 31159747, 31398194, 31050813, 28825054, 31786208, 31980526, 32906215, 33471991, 32923877, 33919281, 34903604). Twenty-three ClinVar submitters have assessed the variant since 2014: fourteen classified the variant as uncertain significance and 9 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV001149533	SCV001310491	uncertain significance	CHEK2-Related Cancer Susceptibility	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000199067	SCV001429610	likely pathogenic	Familial cancer of breast	2023-01-09	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4_MOD, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212407	SCV001474010	uncertain significance	not provided	2022-03-28	criteria provided, single submitter	clinical testing	The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, Toss 2021). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068) and is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.240). Given the currently available information, the clinical significance of this variant is uncertain at this time. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. PMID: 12533788. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Toss A et al. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021 Apr 21;12(5):616. PMID: 33919281. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7. PMID: 16835864.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212407	SCV002009504	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116009	SCV002537408	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-19	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000199067	SCV002580504	uncertain significance	Familial cancer of breast	2021-10-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465520	SCV002761118	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001270935	SCV003838797	uncertain significance	Breast and/or ovarian cancer	2021-07-30	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153376	SCV003843063	likely pathogenic	Predisposition to cancer	2022-01-03	criteria provided, single submitter	clinical testing	The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be associated with cancer susceptibility (PMID: 12533788, 16835864, 16941491, 22114986, 24082139, 25503501, 26681312, 26845104, 26976419, 27433846, 27616075, 27696107, 27779110, 28135145, 31050813, 31220302). In a large breast cancer case-control analysis, the variant was enriched in breast cancer cases compared to controls (PMID: 33471991). It has also been reported in 11x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (http://whi.color.com). Large co-segregation studies have not been performed, however co-segregation in families is variable and the p.E64K has been observed in at least one individual who also harbored the p.I157T (PMID: 30374176, 31050813). Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813), however yeast-based DNA damage repair assays are inconclusive about a pathogenic or benign effect (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic with evidence suggesting lower penetrance.
Myriad Genetics, Inc.	RCV000199067	SCV004020189	likely pathogenic	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338414	SCV004046969	uncertain significance	Li-Fraumeni syndrome 2		criteria provided, single submitter	clinical testing	The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Roeb, et al 2012).This variant has been reported to the ClinVar database as Uncertain Significance.The p.Glu64Lys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0001591 is reported in gnomAD. The amino acid Glu at position 64 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu64Lys in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116009	SCV004228059	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212407	SCV004235062	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000116009	SCV000805259	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-03-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000199067	SCV000986765	not provided	Familial cancer of breast		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001149533	SCV001446371	likely pathogenic	CHEK2-Related Cancer Susceptibility	2019-09-09	no assertion criteria provided	research
CZECANCA consortium	RCV001270935	SCV001451739	likely pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	case-control
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356247	SCV001551362	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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	RCV000212407	SCV001749676	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. 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. Phenotypic details are available under supporting information.
Cancer Genomics Lab, PINUM Cancer Hospital	RCV000116009	SCV004011747	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-18	no assertion criteria provided	clinical testing