Submissions for variant NM_000059.4(BRCA2):c.8303T>A (p.Leu2768His)

dbSNP: rs587782732

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132229	SCV000187312	likely benign	Hereditary cancer-predisposing syndrome	2020-02-12	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	RCV000766316	SCV000279874	uncertain significance	not provided	2018-07-23	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8303T>A at the cDNA level, p.Leu2768His (L2768H) at the protein level, and results in the change of a Leucine to a Histidine (CTT>CAT). BRCA2 Leu2768His, also defined as BRCA2 8531T>A using alternate nomenclature, has been observed in at least one individual with triple negative breast cancer (Couch 2015). This variant exhibited a level of homology-directed repair (HDR) activity consistent with a classification of 'neutral' in a cell-based functional assay (Guidugli 2018). BRCA2 Leu2768His was not observed in large population cohorts (Lek 2016). This variant is located in DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Leu2768His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539628	SCV000635653	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2768 of the BRCA2 protein (p.Leu2768His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 142807). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29394989, 35736817). 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	RCV000132229	SCV000906575	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with histidine at codon 2768 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to have neutral impact on a homology-mediated DNA repair assay (PMID: 29394989, 35736817). This variant has been reported in at least one individual affected with breast cancer (PMID: 25452441; Leiden Open Variation Database DB-ID BRCA2_000815). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766316	SCV001133927	uncertain significance	not provided	2019-08-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220276	SCV001363309	uncertain significance	not specified	2019-11-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8303T>A (p.Leu2768His) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8303T>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Couch_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study, Guidugli_2018, found the variant to not significantly impede homology-directed DNA repair activity. Five ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462040	SCV004213603	uncertain significance	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001353839	SCV004845633	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with histidine at codon 2768 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to have neutral impact on a homology-mediated DNA repair assay (PMID: 29394989, 35736817). This variant has been reported in at least one individual affected with breast cancer (PMID: 25452441; Leiden Open Variation Database DB-ID BRCA2_000815). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353839	SCV000592181	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2, p.Leu2768His variant was identified the ClinVar database (classified as a uncertain significance variant by the Ambry Genetics) and UMD (3X as a unknown significance variant). The p.Leu2768 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu2768 variant may impact the protein. However, this information is not predictive enough to assume 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 unknown significance