Submissions for variant NM_000059.4(BRCA2):c.3767A>C (p.His1256Pro)

gnomAD frequency: 0.00001  dbSNP: rs80358618

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561816	SCV000668598	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	The p.H1256P variant (also known as c.3767A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3767. The histidine at codon 1256 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios X et al. Fam Cancer, 2017 10;16:477-489). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). 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.
Mendelics	RCV000113216	SCV001139071	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561816	SCV001340012	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1256 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with breast and/or ovarian cancer (PMID: 28477318). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312276	SCV001502721	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1256 of the BRCA2 protein (p.His1256Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 32885271). ClinVar contains an entry for this variant (Variation ID: 51519). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV002247431	SCV002520117	uncertain significance	not provided	2022-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual with a personal and/or family history consistent with pathogenic variants in this gene (Gabaldo Barrios 2017); Also known as 3995A>C; This variant is associated with the following publications: (PMID: 25348012, 24817641, 21523855, 28477318)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561816	SCV003846856	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002247431	SCV004219599	uncertain significance	not provided	2022-12-03	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 28477318 (2017), 32885271 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004803167	SCV005424405	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1256 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual affected with breast and/or ovarian cancer (PMID: 28477318). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055546	SCV005726715	uncertain significance	not specified	2024-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3767A>C (p.His1256Pro) 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 was absent in 245592 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3767A>C has been reported in the literature in at-least one individual affected with Hereditary Breast And/or Ovarian Cancer Syndrome (example: Barrios_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28477318). ClinVar contains an entry for this variant (Variation ID: 51519). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113216	SCV000146294	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	RCV001355615	SCV001550548	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His1256Pro variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, Zhejiang University database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in dbSNP (ID: rs80358618) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry genetics, BIC), UMD-LSDB (2x as unclassified variant), and in BIC Database (1x unknown significance). The p.His1256 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.