Submissions for variant NM_000059.4(BRCA2):c.1054T>C (p.Tyr352His)

gnomAD frequency: 0.00001  dbSNP: rs542343726

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167496	SCV000218354	benign	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV000470929	SCV000560437	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001697202	SCV000569857	likely benign	not provided	2019-03-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23096355)
Color Diagnostics, LLC DBA Color Health	RCV000167496	SCV000903401	likely benign	Hereditary cancer-predisposing syndrome	2018-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485522	SCV001426859	uncertain significance	not specified	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1054T>C (p.Tyr352His) 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. The variant allele was found at a frequency of 8.1e-06 in 247576 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1054T>C has been reported in the literature in at least one individual affected with breast cancer (Lara_2012). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. The authors of this study report that this variant may not be the main cause of the disease as this variant generates biochemically similar changes in amino acids. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23096355). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. One of the ClinVar submitters states without providing specific evidence for independent evaluation, that the variant was seen in trans with a mutation or in homozygous state in individual without severe disease for that gene (SCV000218354.3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence of clinical or functional importance becomes available.
Sema4, Sema4	RCV000167496	SCV002533203	likely benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167496	SCV003849808	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001697202	SCV004219492	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 23096355 (2012)). The frequency of this variant in the general population, 0.0000081 (2/247576 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.