Submissions for variant NM_000059.3(BRCA2):c.7435+10G>A

dbSNP: rs81002793

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045210	SCV000073223	benign	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113755	SCV000383766	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.
Illumina Laboratory Services, Illumina	RCV000302479	SCV000383767	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.
GeneDx	RCV000426181	SCV000512385	likely benign	not specified	2016-09-30	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.
Color Diagnostics, LLC DBA Color Health	RCV000579409	SCV000683870	likely benign	Hereditary cancer-predisposing syndrome	2017-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000426181	SCV002046106	benign	not specified	2021-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426181	SCV002572473	likely benign	not specified	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7435+10G>A 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 and at least one study has provided experimental evidence demonstrating that the variant has no impact on splicing (e.g.Fraile-Bethencourt_2019). The variant allele was found at a frequency of 4e-06 in 249908 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7435+10G>A has been reported in the literature in at least one individual from a cohort of breast and ovarian cancer patients, without strong evidence for causality (e.g.Santonocito_2020). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with a pathogenic variant has been reported in the UMD database (BRCA1 c.798_799delTT, p.Ser267LysfsX19), providing supporting evidence for a benign role. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Four classified the variant as benign (n=2)/likely benign (n=2) and two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003952470	SCV004773382	likely benign	BRCA2-related condition	2020-01-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113755	SCV000147081	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045210	SCV001934571	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-03	no assertion criteria provided	clinical testing