Submissions for variant NM_000059.4(BRCA2):c.5896C>T (p.His1966Tyr)

gnomAD frequency: 0.00002  dbSNP: rs80358822

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000225745	SCV000072800	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131689	SCV000186725	likely benign	Hereditary cancer-predisposing syndrome	2020-10-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000044787	SCV000210622	likely benign	not specified	2017-11-02	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.
Vantari Genetics	RCV000131689	SCV000267020	likely benign	Hereditary cancer-predisposing syndrome	2015-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044787	SCV000694915	likely benign	not specified	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5896C>T (p.His1966Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5896C>T has been reported in the literature in individuals affected with cancer phenotypes without strong evidence for causality (e.g. Spearman_2008, Caux-Montcoutier_2011, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in two internal samples (BRCA1 c.213-11T>G; BRIP1 c.2392C>T, p.Arg798X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000031586	SCV000785127	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000225745	SCV000891072	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131689	SCV000910982	likely benign	Hereditary cancer-predisposing syndrome	2017-04-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001800329	SCV001160596	uncertain significance	not provided	2021-02-28	criteria provided, single submitter	clinical testing	The BRCA2 c.5896C>T; p.His1966Tyr variant (rs80358822) is reported in the literature in a large cohort of individuals with a personal or family history of breast or ovarian cancer, but no specific phenotype data is available (Caux-Moncoutier 2011). This variant is reported in ClinVar (Variation ID: 38005), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 1966 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.184). Due to limited information, the clinical significance of the p.His1966Tyr variant is uncertain at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800329	SCV002047268	likely benign	not provided	2022-08-25	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131689	SCV003850760	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).
Sharing Clinical Reports Project (SCRP)	RCV000031586	SCV000054192	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-02-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031586	SCV000146726	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356911	SCV001552198	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His1966Tyr variant was not identified in the literature nor was it identified in the Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs80358822) as With other allele, ClinVar (classified as likely benign by Invitae, GeneDx, Vantari Genetics, SCRP; classified as uncertain significance by Ambry Genetics, BIC), Clinvitae (conflicting interpretations of pathogenicity), MutDB, LOVD 3.0 (3X predicted neutral), UMD-LSDB (4X unclassified variant), BIC Database (5X with unknown clinical significance), ARUP Laboratories (uncertain significance), databases. The variant was identified in control databases in 3 of 277056 chromosomes at a frequency of 0.000011 (Genome Aggregation Consortium Feb 27, 2017). The p.His1966 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
BRCAlab, Lund University	RCV000031586	SCV004243694	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing