ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4535G>A (p.Arg1512His) (rs80358685)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167383 SCV000218237 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113313 SCV000146439 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000167383 SCV000905837 likely benign Hereditary cancer-predisposing syndrome 2015-12-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481718 SCV000591907 uncertain significance not specified 2012-06-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763888 SCV000894823 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000509510 SCV000566610 uncertain significance not provided 2016-10-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4535G>A at the cDNA level, p.Arg1512His (R1512H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 4763G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg1512His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg1512His occurs at a position that is not conserved and is located in the POLH and RAD51 binding domains (Roy 2012, Buisson 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Arg1512His is pathogenic or benign. We consider it to be a variant of uncertain significance.
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000044429 SCV000072442 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1512 of the BRCA2 protein (p.Arg1512His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in a different gene, which suggests that this c.4535G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51661). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000509510 SCV000889050 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing

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