Submissions for variant NM_000059.4(BRCA2):c.5423T>C (p.Ile1808Thr)

gnomAD frequency: 0.00002  dbSNP: rs397507350

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217283	SCV000276364	likely benign	Hereditary cancer-predisposing syndrome	2018-11-14	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.
GeneDx	RCV000432442	SCV000517973	likely benign	not specified	2017-12-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587412	SCV000694868	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of an medium size and hydrophobic Isoleucine (I) with a medium size and polar Threonine (T). 3/5 in silico tools predict the variant to be benign. It was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.0024% which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%). To our knowledge, the variant was not reported in patients and clinically relevant functional studies assessing the functional impact of the variant were not published either. One clinical diagnostic laboratory and one database classify variant as a VUS (without evidence to independently evaluate). Due to the lack of clinical data and functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
PreventionGenetics, part of Exact Sciences	RCV000587412	SCV000805723	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697860	SCV000826493	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1808 of the BRCA2 protein (p.Ile1808Thr). This variant is present in population databases (rs397507350, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32438681, 34178674). ClinVar contains an entry for this variant (Variation ID: 37964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000217283	SCV000911759	likely benign	Hereditary cancer-predisposing syndrome	2017-11-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587412	SCV001470224	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217283	SCV002536138	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-22	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000217283	SCV003847234	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000031545	SCV004846576	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Mendelics	RCV004700292	SCV005205563	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Sharing Clinical Reports Project (SCRP)	RCV000031545	SCV000054150	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-04-15	no assertion criteria provided	clinical testing