Submissions for variant NM_000059.4(BRCA2):c.316+13A>G

gnomAD frequency: 0.00004  dbSNP: rs773097109

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229296	SCV000283204	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000378354	SCV000383608	uncertain significance	Fanconi anemia complementation group D1	2018-01-12	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	RCV001094073	SCV000383609	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000579746	SCV000683530	likely benign	Hereditary cancer-predisposing syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607980	SCV000694670	likely benign	not specified	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.316+13A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 247610 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316+13A>G has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (Caux_Moncoutier_2011). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Benign (n=4) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000607980	SCV000730698	benign	not specified	2015-09-15	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.
PreventionGenetics, part of Exact Sciences	RCV000586995	SCV000805687	likely benign	not provided	2017-10-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579746	SCV002533765	likely benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357840	SCV001553428	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 c.316+13A>G variant was identified in 1 of 3050 proband chromosomes (frequency: 0.0003) from individuals or families with a history of breast (including male), colon, or ovarian cancer (Caux-Moncoutier 2011). The variant was also identified in dbSNP (ID: rs773097109) as "With other allele", ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Color, and Prevention Genetics; and as uncertain significance by Illumina Clinical Services Laboratory and Integrated Genetics/Laboratory Corporation of America), and in UMD-LSDB (14x as unclassified variant). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 7 of 274246 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23628 chromosomes (freq: 0.00004) and European in 6 of 124828 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.