ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.316+13A>G (rs773097109)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229296 SCV000283204 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001094073 SCV000383609 uncertain significance Breast-ovarian cancer, familial 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 Health, Inc 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 uncertain significance not specified 2020-09-08 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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,PreventionGenetics RCV000586995 SCV000805687 likely benign not provided 2017-10-27 criteria provided, single submitter clinical testing
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.

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