Submissions for variant NM_000059.4(BRCA2):c.8262T>G (p.His2754Gln)

gnomAD frequency: 0.00001  dbSNP: rs587776472

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000144193	SCV000489647	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000483045	SCV000571256	uncertain significance	not provided	2016-08-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8262T>G at the cDNA level, p.His2754Gln (H2754Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAT>CAG). Using alternate nomenclature, this variant would be defined as BRCA2 8490T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His2754Gln 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 Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 His2754Gln occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 His2754Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575580	SCV000661431	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing	The p.H2754Q variant (also known as c.8262T>G), located in coding exon 17 of the BRCA2 gene, results from a T to G substitution at nucleotide position 8262. The histidine at codon 2754 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in several Italian breast and/or ovarian cancer cohorts (Zuntini R et al. Front Genet, 2018 Sep;9:378; Santonocito C et al. Cancers (Basel), 2020 May;12:(5); Incorvaia L et al. Cancers (Basel). 2020 May;12(5); Fanale D et al. Front Oncol. 2021 Jun;11:682445). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637765	SCV000759242	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2754 of the BRCA2 protein (p.His2754Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 30254663, 32380732). ClinVar contains an entry for this variant (Variation ID: 156176). 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.
Color Diagnostics, LLC DBA Color Health	RCV000575580	SCV001355768	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 2754 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at leas three individuals affected with breast or ovarian cancer (PMID: 30254663, 32380732, 32438681, 34178674). One of these individuals also carried a pathogenic variant in the BRCA1 gene that could explain the observed phenotype (PMID: 32438681). 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	RCV001824645	SCV002074313	uncertain significance	not specified	2022-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8262T>G (p.His2754Gln) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248786 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8262T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without evidence for causaility (examples: Zuntini_2018, Santonocito_2020, Incorvaia_2020, and Fanale_2021). These reports 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 has been reported (BRCA1 c.5266ddupC, p.gln1756ProfsTer74), providing supporting evidence for a benign role (Santonocito_2020). 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 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004804667	SCV004845627	uncertain significance	BRCA2-related cancer predisposition	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 2754 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at leas three individuals affected with breast or ovarian cancer (PMID: 30254663, 32380732, 32438681, 34178674). One of these individuals also carried a pathogenic variant in the BRCA1 gene that could explain the observed phenotype (PMID: 32438681). 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.
Baylor Genetics	RCV004567162	SCV005059048	uncertain significance	Familial cancer of breast	2024-02-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483045	SCV005625314	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing	The BRCA2 c.8262T>G (p.His2754Gln) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 34178674 (2021), 32380732 (2020)) and an individual undergoing BRCA1/2 testing (PMID: 30254663 (2018)). Additionally, this variant has been reported in an individual with ovarian cancer also carrying a pathogenic BRCA1 variant (PMID: 32438681 (2020)). The frequency of this variant in the general population, 0.0000066 (1/152192 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000144193	SCV000189266	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-01	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000144193	SCV004228446	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting) 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)