Submissions for variant NM_000059.4(BRCA2):c.5753A>G (p.His1918Arg)

gnomAD frequency: 0.00001  dbSNP: rs80358804

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113478	SCV001161521	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000833
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085396	SCV000072757	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129155	SCV000183879	likely benign	Hereditary cancer-predisposing syndrome	2018-10-30	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	RCV000588333	SCV000565714	likely benign	not provided	2023-01-04	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588333	SCV000600663	likely benign	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588333	SCV000694900	uncertain significance	not provided	2016-11-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5753A>G (p.His1918Arg) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121048 (1/30303), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. A publication cites the variant indicating it is located near a predicted phosphorylation site (Tram_2013). In addition, multiple clinical diagnostic laboratories/databases cite the variant with conflicting classifications "uncertain significance" or "likely benign." One database cites the variant to co-occur with a potentially pathogenic BRCA2 variant, c.1689G>A (p.Trp563X). Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a VUS - possibly benign variant.
Counsyl	RCV000113478	SCV000786265	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129155	SCV000903149	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129155	SCV002536173	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113478	SCV000146690	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1997-11-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353529	SCV000591999	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His1918Arg variant was not identified in the literature. This variant was identified in dbSNP (ID: rs80358804) “With untested allele”; however, frequency data was not available, thus the prevalence of this variant in the general population could not be determined. The variant was also listed in the BIC database (4X with unknown clinical importance, but it was not identified in any of the other databases searched including HGMD, LOVD, COSMIC, and UMD. The p.His1918 residue is not conserved in mammals and the variant amino acid arginine (Arg) is present in mouse, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict the creation of a novel splice donor site at the variant nucleotide position; 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.