ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9353T>C (p.Met3118Thr) (rs56204128)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045797 SCV000073810 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 3118 of the BRCA2 protein (p.Met3118Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs56204128, ExAC 0.04%). This variant has been reported in individuals affected with breast cancer (PMID: 9609997, 11091690, 12491487), as well as in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in the BRCA1 gene, which suggests that this c.9353T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 38232). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggest that this missense change is likely to be tolerated. In addition, the threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, none of these predictions have been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131368 SCV000186344 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148437 SCV000190136 uncertain significance Neoplasm of the breast 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000484041 SCV000568497 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9353T>C at the cDNA level, p.Met3118Thr (M3118T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Using alternate nomenclature, this variant would be defined as BRCA2 9581T>C. This variant was observed in an individual with breast cancer and osteosarcoma and family history of breast cancer for whom TP53 analysis was not reported (Katagiri 1998, Kuno 1999). BRCA2 Met3118Thr was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Met3118Thr occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Met3118Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484041 SCV000600855 uncertain significance not specified 2017-01-19 criteria provided, single submitter clinical testing
Color RCV000131368 SCV000906440 likely benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000484041 SCV000917018 uncertain significance not specified 2018-09-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9353T>C (p.Met3118Thr) results in a non-conservative amino acid change located in the BRCA2, OB3 fold (IPR015188) of the encoded protein sequence that belongs to the DNA binding domain. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9353T>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality (Katagiri 1998), thus this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.2940delA (p.Pro981fsX19) in the BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031815 SCV000054423 uncertain significance Breast-ovarian cancer, familial 2 2011-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031815 SCV000147615 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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