Submissions for variant NM_000059.4(BRCA2):c.4535G>A (p.Arg1512His)

gnomAD frequency: 0.00001  dbSNP: rs80358685

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044429	SCV000072442	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000167383	SCV000218237	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	The p.R1512H variant (also known as c.4535G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4535. The arginine at codon 1512 is replaced by histidine, an amino acid with highly similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000509510	SCV000566610	uncertain significance	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Absent from cases but present in controls in a breast cancer case-control study (Momozawa et al., 2018); Also known as 4763G>A; This variant is associated with the following publications: (PMID: 31131967, 34736091, 27149842, 25348012, 25266736, 30287823)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509510	SCV000889050	uncertain significance	not provided	2018-05-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763888	SCV000894823	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167383	SCV000905837	likely benign	Hereditary cancer-predisposing syndrome	2015-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000481718	SCV000919015	uncertain significance	not specified	2018-10-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4535G>A (p.Arg1512His) results in a non-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 7.5e-06 in 267704 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4535G>A has been reported in the literature in individuals affected with cancer (Chmielecki_2014, Giannakis_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5576_5579delTTAA, p.I1859fsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167383	SCV003850586	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113313	SCV000146439	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353969	SCV000591907	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg1512His variant has been identified in individuals with breast and ovarian cancer; however no control chromosomes were included in these studies (Sanz 2010, Lindor 2011, Michal et al.). It is listed in the dbSNP database as coming from a “clinical source” (ID#:rs80358685) however no frequency information was provided. This residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. Other variants impacting the same amino acid position (p.Arg1512Cys (2X) and p.Arg1512Pro (1X)) have been presented in the BIC database as having unknown clinical significance. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is classified as a variant of unknown significance (VUS).
GenomeConnect, ClinGen	RCV000509510	SCV000607027	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.