ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.956A>G (p.Asn319Ser) (rs55939572)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080083 SCV000073869 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000128972 SCV000172857 benign Hereditary cancer-predisposing syndrome 2015-01-15 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000587951 SCV000210553 likely benign not provided 2021-01-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10923033, 11929857, 20104584, 25479140, 21520273, 31131967)
Counsyl RCV000083161 SCV000487870 uncertain significance Breast-ovarian cancer, familial 2 2015-11-24 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045856 SCV000588074 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045856 SCV000695252 uncertain significance not specified 2019-10-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.956A>G (p.Asn319Ser) results in a conservative amino acid change in the encoded protein sequence. 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 1.7e-05 in 229618 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.956A>G has been reported in the literature in one patient with pancreatic cancer (Grant_2015) and in at least one individual affected with unilateral breast cancer (Borg_2010, Capanu_2010) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: three cited the variant as uncertain significance, one cited the variant as likely benign, and one cited the variant as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000128972 SCV000902830 benign Hereditary cancer-predisposing syndrome 2016-01-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587951 SCV001133986 likely benign not provided 2019-06-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109313 SCV001266635 uncertain significance Fanconi anemia, complementation group D1 2018-01-15 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000083161 SCV001266636 uncertain significance Breast-ovarian cancer, familial 2 2018-01-15 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Research and Development, ARUP Laboratories RCV001646960 SCV001854656 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000083161 SCV000115235 likely benign Breast-ovarian cancer, familial 2 2009-02-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083161 SCV000145793 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000587951 SCV000591721 uncertain significance not provided no assertion criteria provided clinical testing The p.Asn319Ser variant has been previously observed in our laboratory, and has been reported in the literature in 2/8412 proband chromosomes of individuals with breast cancer and in 3/8586 control chromosomes tested (Borg 2010, Warren 2002, Capanu_2011_). It is listed in the dbSNP database as coming from a "clinical source" (ID#:rs55939572), but no frequency information was provided, and so the prevalence of this variant in the population is not known. It has been observed in the BIC (x9) and Exome Variant Server databases. The p.Asn319 residue is conserved in mammals, and the variant Serine (Ser) is present in the chicken at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function, though this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined at this time. Therefore this variant is a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735630 SCV000863768 uncertain significance Breast and/or ovarian cancer 2012-10-18 no assertion criteria provided clinical testing

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