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 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129541 SCV000184321 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing The p.S1424C variant (also known as c.4271C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 4271. The serine at codon 1424 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been detected in several breast or ovarian cancer patients as well as in a squamous cell lung cancer patient (Spearman AD et al. J. Clin. Oncol. 2008 Nov;26:5393-400; Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Santos C et al. J Mol Diagn. 2014 May;16:324-34; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Lu C et al. Nat Commun. 2015 Dec;6:10086). This variant was predicted to be neutral based on a study of breast tumor characteristics of known BRCA1/2 alteration carriers (Spearman AD et al. J. Clin. Oncol. 2008 Nov;26:5393-400). Another study predicted that this variant has a neutral effect by analyzing co-segregation, co-occurrence, and in silico data in a Portuguese family with breast and ovarian cancer. Of note, this variant did not segregate with the one ovarian cancer case in this family, and was also found to co-occur with a pathogenic BRCA1 mutation (Santos C et al. J Mol Diagn. 2014 May;16:324-34). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Health, Inc RCV000129541 SCV000688863 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-05 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 1424 of the BRCA2 protein. Serine at this position shows poor evolutionary conservation and variant cysteine is observed in multiple mammalian species, suggesting that this variant may be tolerated for BRCA2 function. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 19491284, 24607278, 21120943, 25682074, 28324225). In a family with multiple individuals affected with breast and ovarian cancer, this variant was reported to be absent in an individual affected with early-onset breast cancer (PMID: 24607278). The proband from this family was affected with breast cancer and carried a pathogenic variant in the BRCA1 gene (PMID: 24607278). This variant has been identified in 3/276480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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