Submissions for variant NM_000059.4(BRCA2):c.3211C>T (p.His1071Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80358564

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212225	SCV000210310	uncertain significance	not provided	2014-10-20	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3211C>T at the cDNA level, p.His1071Tyr (H1071Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has been reported in the Breast Cancer Information Core (BIC) database as having unknown clinical importance. BRCA2 His1071Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His1071Tyr occurs at a position that is highly variable across species and is located in the RAD51 binding domain (Roy 2012). 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 His1071Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000113148	SCV000489593	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572282	SCV000661193	likely benign	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000572282	SCV000903952	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1071 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 an individual affected with pancreatic cancer (PMID: 28767289, 29309945, 32659497). This variant has also been identified in 2/245560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 1 woman older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/ ). 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	RCV001299345	SCV001488430	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1071 of the BRCA2 protein (p.His1071Tyr). This variant is present in population databases (rs80358564, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 32659497). ClinVar contains an entry for this variant (Variation ID: 51424). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212225	SCV002010385	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212225	SCV002047252	uncertain significance	not provided	2024-10-21	criteria provided, single submitter	clinical testing	The BRCA2 c.3211C>T (p.His1071Tyr) variant has been reported in the published literature in individuals affected with pancreatic ductal adenocarcinoma (PDAC) (PMID: 28767289 (2017), 29309945 (2018), 32659497 (2020)) and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000081 (2/245560 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572282	SCV003851771	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).
All of Us Research Program, National Institutes of Health	RCV000113148	SCV004845127	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1071 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 28767289). This variant has also been identified in 2/245560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 1 woman older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/ ). 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	RCV004799761	SCV005423183	uncertain significance	not specified	2024-10-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3211C>T (p.His1071Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245560 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3211C>T has been reported in the literature in an individual affected with pancreatic cancer (Shindo_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 publications have been ascertained in the context of this evaluation (PMID: 29309945, 28767289). ClinVar contains an entry for this variant (Variation ID: 51424). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005003440	SCV005633898	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-05-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113148	SCV000146191	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing