ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4271C>G (p.Ser1424Cys) (rs80358664)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113287 SCV001161518 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000524
Invitae RCV000044384 SCV000072397 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1424 of the BRCA2 protein (p.Ser1424Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (rs80358664, ExAC no frequency). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 19491284, 24607278, 21120943, 25682074), and in an individual affected with lung cancer (PMID: 26689913). In one family this variant was found not to segregate with disease (PMID: 24607278). This variant has also been reported in an individual in whom a pathogenic allele was also identified in the BRCA2 gene, which suggests that this c.4271C>G variant was not the primary cause of disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 51623). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The cysteine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not 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 RCV000129541 SCV000184321 uncertain significance Hereditary cancer-predisposing syndrome 2014-01-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Michigan Medical Genetics Laboratories,University of Michigan RCV000113287 SCV000195983 uncertain significance Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000590783 SCV000329136 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4271C>G at the cDNA level, p.Ser1424Cys (S1424C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 4499C>G. This variant was observed in at least three individuals with breast cancer and one individual with lung cancer (Spearman 2008, Haffty 2009, Lu, 2015, Wong-Brown 2015). This variant was predicted to be neutral by a model based on aspects of tumor pathology and genetics including receptor status, tumor grade, loss of heterozygosity, and presence of deleterious variants in trans (Spearman 2008). In addition, this variant was identified in a individual with breast cancer and a family history of breast and ovarian cancer (Santos 2014). However, this family was also identified to carry a pathogenic BRCA1 variant and BRCA2 Ser1424Cys was not identified in the individual with an early-onset ovarian cancer (Santos 2014). BRCA2 Ser1424Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRC3 domain and the POLH binding domain (Cole 2011, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser1424Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129541 SCV000688863 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590783 SCV000694761 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4271C>G (p.Ser1424Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant lies within the BRC3 domain (UMD) and the POLH binding domain (UniProt). 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in the large control database ExAC (0/119534 control chromosomes). Several publications have cited the variant and categorized it as neutral (Spearman_JCO_2008; Santos_BRCA1&2_JMD_2014) or variant of unknown significance (Caux-Moncoutier_HM_2011; Hafty_BRCA1&2_Annals of Oncology_2009; Wong-Brown_BRCA1&2_BCRT_2015). Additionally, Santos_BRCA1&2_JMD_2014 found that the variant did not co-segregate completely in family study (4 of 5 affected family members had the variant) and identified a co-occurring BRCA1 pathogenic mutation in the same family, although precise information on the mutation and which family members were carriers was not provided. Another BRCA1 pathogenic co-occurrence with the variant was also found in the BIC database, although overlap with the Santos study cannot be unequivocally ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000590783 SCV000885083 likely benign not provided 2017-07-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113287 SCV000146397 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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