ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2957A>G (p.Asn986Ser) (rs28897718)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129122 SCV000183839 likely benign Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113119 SCV000146146 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129122 SCV000902858 benign Hereditary cancer-predisposing syndrome 2016-09-07 criteria provided, single submitter clinical testing
Counsyl RCV000113119 SCV000488650 uncertain significance Breast-ovarian cancer, familial 2 2016-05-19 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735534 SCV000863672 uncertain significance Breast and/or ovarian cancer 2002-09-19 no assertion criteria provided clinical testing
GeneDx RCV000168561 SCV000210583 likely benign not specified 2018-02-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000586870 SCV000694656 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2957A>G (p.Asn986Ser) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 1/120330 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). However, it could still represent as a very rare polymorphism. It has been reported in two breast cancer patients in literature without strong evidence for or against pathogenicity (Borg_2008, Wong-Brown_2015). It has also been reported by a reputable clinical database (BIC) in seven individuals undergoing BRCA1/2 testing. In one of the individuals, the variant co-occurred with another deleterious variant c. c.2808_2811delACAA, supporting for a benign outcome. In addition, multiple clinical laboratories have classified this variant as benign/likely benign and one lab classified this variant as VUS, all without evidence to independently evaluate. Taken together, this variant has been classified as VUS-possibly benign.
Invitae RCV000203667 SCV000072106 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 986 of the BRCA2 protein (p.Asn986Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs28897718, ExAC 0.002%). This variant has been reported in individuals affected with breast cancer (PMID: 20104584, 25682074, 21520273) and 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 BRCA2 gene, which suggests that this c.2957A>G substitution was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51377). 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 serine amino acid residue is 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional 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.

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