Submissions for variant NM_000059.4(BRCA2):c.1244A>G (p.His415Arg)

gnomAD frequency: 0.00001  dbSNP: rs80358417

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084688	SCV000071779	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000160035	SCV000210265	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 1472A>G; Observed in individuals with breast and/or ovarian cancer, pancreatic cancer, as well as, unaffected controls (Wong-Brown 2015, Alemar 2017, Momozawa 2018, Zuntini 2018, Mizukami 2020, Santonocito 2020); This variant is associated with the following publications: (PMID: 10923033, 25682074, 29161300, 30254663, 32438681, 30287823, 32980694)
Ambry Genetics	RCV000165768	SCV000216513	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-23	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 alteration has also been identified in individuals diagnosed with breast and/or ovarian cancer (Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Zuntini R et al. Front Genet, 2018 Sep;9:378; Santonocito C et al. Cancers (Basel), 2020 May;12:). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0003 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0003 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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, susceptibility to, 2	2016-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2022-10-03	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 as a VUS in individuals undergoing testing for Breast and/or Ovarian Cancer (example, Alemar_2017, Momozawa_2018, Wong-Brown_2015, Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the UMD database (BRCA1 c.3979C>T, p.Gln1327Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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 (VUS, n=6; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160035	SCV002046114	uncertain significance	not provided	2020-11-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000780016	SCV002517966	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165768	SCV002533219	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-19	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000112899	SCV002761582	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-12-31	criteria provided, single submitter	clinical testing	Insufficient evidence
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165768	SCV003849937	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)	RCV000112899	SCV000145839	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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.
Department of Medical and Surgical Sciences, University of Bologna	RCV000112899	SCV004228364	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)