Submissions for variant NM_000059.4(BRCA2):c.9949C>T (p.Leu3317=)

gnomAD frequency: 0.00007  dbSNP: rs777488349

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494760	SCV000579090	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000163907	SCV000214501	likely benign	Hereditary cancer-predisposing syndrome	2014-09-11	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.
Invitae	RCV000228048	SCV000283376	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469115	SCV000541064	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163907	SCV000689235	likely benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501438	SCV000918921	likely benign	not specified	2018-06-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9949C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 276918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9949C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other likely pathogenic/pathogenic variants have been reported in our internal database (BRCA2 c.9924C>G (p.Tyr3308X), PALB2 c.801_802dupTA (p.Lys268fsX12)), providing supporting evidence for a benign role. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283949	SCV001469468	likely benign	not provided	2019-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001283949	SCV001891120	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163907	SCV002532075	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353936	SCV000592308	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu3317Leu variant does not alter an amino acid residue and is located outside of the splicing consensus sequence. None of the computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to rule out pathogenicity. It has not been previously reported in the literature or mutation datrabases. It is not listed in dbSNP, 1000 Genomes, or EVS databases, and so the frequency of this variant in the general population is not known. In summary, 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 Predicted Benign.