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
Invitae RCV000044429 SCV000072442 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000167383 SCV000218237 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-29 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 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 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.
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 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
Color Health, Inc 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113313 SCV000146439 uncertain significance Breast-ovarian cancer, familial 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.

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