Submissions for variant NM_000059.4(BRCA2):c.6886A>C (p.Ile2296Leu)

dbSNP: rs576279166

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132216	SCV000187298	likely benign	Hereditary cancer-predisposing syndrome	2019-02-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203848	SCV000261976	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000353391	SCV000383748	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	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	RCV000410842	SCV000383749	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000410842	SCV000488288	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001284584	SCV000571484	likely benign	not provided	2021-02-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32046981, 30555256, 21811163)
Color Diagnostics, LLC DBA Color Health	RCV000132216	SCV000910979	likely benign	Hereditary cancer-predisposing syndrome	2016-11-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000479638	SCV000918806	likely benign	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6886A>C (p.Ile2296Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predict the variant no significant impact on splicing. One predict the variant strengthens a cryptic 3' acceptor site. One predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 249818 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075). c.6886A>C has been reported in the literature in an individual affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence of causality (Mehta_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was tested by mini-gene assay and was reported to lead to very slight exon 12 skipping (Meulemans_2020).. ClinVar contains an entry for this variant (Variation ID: 142797). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284584	SCV001470444	likely benign	not provided	2022-03-29	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000203848	SCV002025803	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000410842	SCV002764605	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-11-18	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 12 of the BRCA2 gene that results in the amino acid substitution of leucine for isoleucine at codon 2296 was detected. The reference codon is conserved across primates. The variant meets our criteria to be classified as a variant of uncertain significance.
True Health Diagnostics	RCV000132216	SCV000787946	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-05	no assertion criteria provided	clinical testing