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

dbSNP: rs55939572

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080083	SCV000073869	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	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: seen in unaffected individuals, 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, susceptibility to, 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	likely benign	not specified	2023-05-01	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 individuals with pancreatic cancer (Grant_2015, Power_2021) 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 Syndrome. A large scale multifactorial quantitative analysis to support clinical variant classification has rendered a likely benign outcome (Parsons_2019). One publication reports experimental evidence evaluating an impact on CDC25A mRNA expression, however, does not allow convincing conclusions about the variant effect (Biswas_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29416040, 20104584, 21520273, 25479140, 28132688, 31131967, 32918181, 30212499, 11929857). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus leaning towards a benign(n=2)/likely benign (n=5) outcome (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	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	2021-06-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, Illumina	RCV000083161	SCV001266636	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
Sema4, Sema4	RCV000128972	SCV002532049	likely benign	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000128972	SCV003848162	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000083161	SCV000115235	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083161	SCV000145793	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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