ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8009C>T (p.Ser2670Leu) (rs80359035)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045385 SCV000073398 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2670 of the BRCA2 protein (p.Ser2670Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31742824, 31409081, 23096355, 26250392, 31843900, 22895246, 15131399, 24249303, 26187060, 28176296). This variant was also observed to co-occur with a pathogenic BRCA2 variant (c.538_539dupAT) in an individual with Fanconi anemia (PMID: 24735155). It is also known as 8237C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52471). Experimental studies have shown that this variant affects BRCA2 protein function (PMID: 19043619, 29394989). In addition, a multifactorial likelihood algorithm using genetic and statistical data determined this variant has a high probability of being pathogenic (PMID: 31131967). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 31191615, 28339459). 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.
Ambry Genetics RCV000131082 SCV000186012 pathogenic Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing The p.S2670L variant (also known as c.8009C>T), located in coding exon 17 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8009. The serine at codon 2670 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with clinical histories suggestive of HBOC (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Jimenez AM et al. Clin. Adv. Hematol. Oncol. 2012 Jun;10:402-4; Lara K et al. Biol. Res. 2012;45(2):117-30; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9; Pal T et al. Cancer. 2015 Dec;121:4173-80). This alteration has been identified with multiple pathogenic BRCA2 alterations in multiple families with Fanconi Anemia (Rosenthal ET et al. Clin. Genet. 2015 Dec;88(6):533-41; Trejo Bittar HE et al. Pediatr. Dev. Pathol. Apr;17:297-301). This variant was found to be functionally defective in a homology-directed repair assay (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80). This alteration was shown to result in a minor amount of exon 17 skipping (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691). Of note, this alteration is also designated as 8237C>T in published literature. This amino acid position is highly conserved through mammals, but not in lower available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx RCV000212267 SCV000210458 likely pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8009C>T at the cDNA level, p.Ser2670Leu (S2670L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, previously reported as 8237C>T using alternate nomenclature, was observed in several individuals with breast cancer (Chenevix-Trench 2006, Lara 2012, Morris 2012, Jimenez 2012, Lynce 2015, Pal 2015, Kwong 2016). BRCA2 S2670L was observed with a second pathogenic BRCA2 variant in a young male with Fanconi Anemia (Trejo Bittar 2014). Rosenthal et al. (2015) reported this variant in trans with another BRCA2 variant in two siblings, one with a personal history of leukemia, early onset breast cancer and clinical features suggestive of Fanconi Anemia and the other unaffected. A breast tumor from an individual with BRCA2 S2670L demonstrated loss of the variant allele (Chenevix-Trench 2006). However, a functional study found that this variant resulted in impaired homology directed repair in vitro (Karchin 2008). BRCA2 Ser2670Leu was not observed in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2670Leu occurs at a position that is conserved in mammals and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider BRCA2 Ser2670Leu to be a likely pathogenic variant.
Clinical Molecular and Personalized Diagnostics,Institute of Biochemistry and Clinical Biochemistry, Teaching and Research Hospital Agostino Gemelli Foundation RCV000409052 SCV000484655 pathogenic Breast-ovarian cancer, familial 1 2016-12-14 criteria provided, single submitter clinical testing Personal and familial history of breast and ovarian cancers
Color Health, Inc RCV000131082 SCV000683935 pathogenic Hereditary cancer-predisposing syndrome 2020-07-31 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 2670 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An RNA study found the variant resulted in splicing defects predicted to cause an absent or non-functional protein product (PMID: 31843900). Functional studies reported this variant is severely impaired in homology-directed repair assays (PMID: 19043619, 29394989). This variant has been observed in multiple individuals affected with breast cancer (PMID: 22895246, 25639900, 26681312, 31843900) and pancreatic cancer (PMID: 29395620). This variant also has been observed in multiple families affected with breast and/or ovarian cancer (PMID: 15131399, 24249303, 30254663) and it is reported to co-segregate with disease in two families with likelihood ratio of 17.8658 (PMID: 31131967). This variant is also seen in an individual with a pathogenic BRCA2 covariant affected with Fanconi anemia and has a family history of breast and other solid-tumor cancers (PMID: 24735155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl RCV000077423 SCV000786255 likely pathogenic Breast-ovarian cancer, familial 2 2018-03-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212267 SCV000889147 likely pathogenic not provided 2020-08-26 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045385 SCV001426773 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8009C>T (p.Ser2670Leu) results in a non-conservative amino acid change located in the DSS1 interaction domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251148 control chromosomes. c.8009C>T has been reported in the literature in multiple individuals affected with Hereditary/Familial Breast And Ovarian Cancer and at-least two individuals with Fanconi Anemia in whom a co-occurring BRCA2 variant in trans was identified (example, Lubinski_2004, Lara_2012, Chenevix-Trench_2006, Hondow_2011, Nakamura_2015, Jimnez_2012, Lynce_2015, Machakova_2019, Rosenthal_2015, Shao_2020, Susswein_2016, Zuntini_2018, Trejo Bittar_2014). These data indicate that the variant allele was transmitted much more often than the reference allele to affected individuals within families and is therefore likely to be associated with disease. The cases with other co-occurring pathogenic variants include, BRCA2 c.9699_9702delTATG, p.Cys3233_Met3234?fs (p.Cys3233fs) and BRCA2 c.767insA (variant not reported in other databases) respectively in two patients with Fanconi Anemia (Rosenthal_2015 and Trejo Bittar_2014); and BRCA1 c.212+3A>G (UMD database). At least three independent publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed DNA repair (HDR) capability (Hart_2019, Guidugli_2018, Karchin_2008). Loss of heterozygosity (LOH) of the variant allele was observed in at-least one of two tumors examined, while no LOH was observed in the second tumor (Chenevix-Trench_2006). To our knowledge, this finding has not been independently reproduced and the authors speculated that the loss of the wild-type allele is less common for some pathogenic missense variants that act as dominant-negative mutations. Therefore, this evidence is not weighted in favor of a neutral impact of this variant in-vivo. Two recent publications, one reporting the fifth Critical Assessment of Genome Interpretation (CAGI) and another reporting a multifactorial analysis based classification, both support a "likely pathogenic" outcome for this variant (Padilla_2019, Parsons_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045385 SCV001478293 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (28.4) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.99 and an overall classification of pathogenic. (PS3_strong). This variant has been classified on ClinVar as likely pathogenic by multiple accredited USA diagnostic laboratories (PP5_sup). Data not used in classification: There are additional reports of this variant in UMD (6), BIC (9), and BRCA2 LOVD (2).
Sharing Clinical Reports Project (SCRP) RCV000077423 SCV000109221 likely pathogenic Breast-ovarian cancer, familial 2 2010-01-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077423 SCV000147248 not provided Breast-ovarian cancer, familial 2 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496611 SCV000587931 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001270290 SCV000592170 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser2670Leu variant has been reported in individuals affected with breast cancer (PMID: 23096355, 26250392) and inflammatory breast cancer (PMID: 22895246), as well as in individuals with a personal and/or family history of breast/ovarian cancer (PMID: 15131399, 24249303, 26187060). This variant was also observed to co-occur with a pathogenic BRCA2 variant (c.538_539dupAT) in an individual with Fanconi anemia, however the phase of the variants was not confirmed (PMID: 24735155). The variant was identified in ClinVar (Conflicting interpretations of pathogenicity. Likely pathogenic: Ambry in 2017, GeneDx in 2017, Counsyl in 2017, Invitae in 2018, Color in 2018, Quest Diagnostics in 2019, Sharing Clinical Reports Project in 2010. VUS by Research Molecular Genetics Laboratory at Women's College Hospital in 2014. Pathogenic by Clinical molecular and personalized diagnostics in 2016. GeneInsight-COGR (Sinai Health System and COGR consensus) classify as VUS, 2013), LOVD 3.0 (17 entries, VUS 10x, likely pathogenic 3x, pathogenic 1x) and __ARUP Laboratories (3-Uncertain) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). A truncating variant at the same location, c.8009C>A (p.Ser2670*), is classified in ClinVar as Pathogenic (3 stars, reviewed by expert panel). The variant is located in the BRCA2 DNA binding domain (Yang 2002, Guidugli 2017), increasing the likelihood that it may have clinical significance. Through a homology-directed DNA repair assay, the p.Ser2670Leu variant was found to substantially decrease HDR compared to wild-type BRCA2 and known neutral variants, and was predicted to be deleterious (Guidugli_2017_PMID:29394989). However, Karchin (2008) and Chenevix-Trench (2006) described this variant on an allele that was lost by LOH in breast tissue, a result that has been associated with increased probability of neutrality. Furthermore, Myriad genetics has also reported this variant to co-occur with a second pathogenic variant (Chenevix-Trench 2006) increasing the likelihood this variant may be benign. The p.Ser2670 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
King Laboratory,University of Washington RCV001171451 SCV001251362 pathogenic Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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