ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1244A>G (p.His415Arg) (rs80358417)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084688 SCV000071779 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000160035 SCV000210265 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1244A>G at the cDNA level, p.His415Arg (H415R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 1472A>G. This variant has been identified in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Wong-Brown 2015, Alemar 2017). BRCA2 His415Arg was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His415Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165768 SCV000216513 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-11 criteria provided, single submitter clinical testing The p.H415R variant (also known as c.1244A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1244. The histidine at codon 415 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 418 Brazilian individuals who met NCCN genetic testing guidelines for hereditary breast and ovarian cancer (Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630). This amino acid position is not well 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.
Counsyl RCV000112899 SCV000488424 uncertain significance Breast-ovarian cancer, familial 2 2016-03-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165768 SCV000903093 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780016 SCV000917010 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1244A>G (p.His415Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249452 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1244A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Alemar_2017, Momozawa_2018, Wong-Brown_2015, Zuntini_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (UMD: BRCA1 c.3979C>T (p.Gln1327X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 as VUS, 2 as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112899 SCV000145839 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735440 SCV000863576 uncertain significance Breast and/or ovarian cancer 2014-01-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112899 SCV001554187 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.His415Arg variant was identified in 2 of 1506 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alemar 2017, Wong 2015). The variant was also identified in large population study by Momozawa (2018) in 5 of 14102 female chromosomes (frequency: 0.0004), and 7 in 22482 female control chromosomes (frequency: 0.0003) and 4 in 24980 male control chromosomes (frequency: 0.0002). The variant was also identified in dbSNP (ID: rs80358417) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Color; as uncertain significance by six submitters), LOVD 3.0 (6x), and UMD-LSDB (9x as likely neutral). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3979C>T(p.Gln1327X)), increasing the likelihood that the p.His415Arg variant does not have clinical significance. The variant was also identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic BRCA1 variant (c.5278-?_5592+?del, p.Ile1760_His1862delins37), further increasing the likelihood this variant has little clinical significance. The variant was identified in control databases in 5 of 275910 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6428 chromosomes (freq: 0.0002), European in 4 of 126226 chromosomes (freq: 0.00003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His415 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information 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 likely benign.

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