ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8009C>T (p.Ser2670Leu) (rs80359035)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131082 SCV000186012 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Deficient protein function in appropriate functional assay(s)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077423 SCV000147248 not provided Breast-ovarian cancer, familial 2 no assertion provided clinical testing
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 RCV000131082 SCV000683935 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing
Counsyl RCV000077423 SCV000786255 likely pathogenic Breast-ovarian cancer, familial 2 2018-03-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000496611 SCV000592170 uncertain significance not specified 2013-12-19 criteria provided, single submitter clinical testing
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.
Invitae RCV000045385 SCV000073398 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-11 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 (rs80359035, ExAC no frequency). This 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 (PMID: 24735155). It is also known as 8237C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52471). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). Also, experimental studies have shown that this missense change impairs the homology-directed repair activity of the BRCA2 protein (PMID: 19043619, 29394989). In summary, this variant is a rare missense change that has been reported in affected individuals, and shown to disrupt BRCA2 protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212267 SCV000889147 likely pathogenic not provided 2018-04-20 criteria provided, single submitter 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
Sharing Clinical Reports Project (SCRP) RCV000077423 SCV000109221 likely pathogenic Breast-ovarian cancer, familial 2 2010-01-25 no assertion criteria provided clinical testing

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