Submissions for variant NM_000059.3(BRCA2):c.3226G>A (p.Val1076Ile) (rs431825304)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222899	SCV000275335	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-19	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America	RCV000588617	SCV000694680	uncertain significance	not provided	2017-01-02	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.3226G>A (p.Val1076Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is absent in 119346 control chromosomes from ExAC. This variant has been reported in HBOC or HBOC-related families/patients and individuals undergoing BRCA1/2 testing in literature (Kote-Jarai_2011, Peixoto_2014) as well as clinical databases (UMD, ClinVar) without strong evidence for pathogenicity. In two instances, this variant was found to co-occur with other deleterious variants [BRCA2 c.3159delA (p.Asp1054IlefsX6) (UMD) and BRCA2 p.Ser871X (internal sample)], strongly suggesting for a benign outcome. Two clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance, however without evidence to independently evaluate. Taken together, this variant is classified as VUS-possibly benign.
Invitae	RCV000799401	SCV000939061	uncertain significance	Hereditary breast and ovarian cancer syndrome	2019-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 1076 of the BRCA2 protein (p.Val1076Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family suspected to be affected with hereditary breast and/or ovarian cancer (PMID: 24916970), and an individual affected with prostate cancer (PMID: 21952622). It has also been observed in an individual referred for BRCA2 testing (PMID: 27633797). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that the c.3226G>A variant was not the primary cause of disease. In this literature, due to an apparent typographical error, these variants are indicated to occur in BRCA1 instead of BRCA2. ClinVar contains an entry for this variant (Variation ID: 96788). 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 isoleucine 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 and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina	RCV000082909	SCV001271420	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001113630	SCV001271421	uncertain significance	Fanconi anemia, complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP)	RCV000082909	SCV000114983	uncertain significance	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing