Submissions for variant NM_000059.4(BRCA2):c.7042A>C (p.Asn2348His)

gnomAD frequency: 0.00001  dbSNP: rs55742659

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484747	SCV000572304	uncertain significance	not provided	2016-11-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7042A>C at the cDNA level, p.Asn2348His (N2348H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 7270A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2348His 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 Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2348His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Asn2348His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509958	SCV000608251	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The p.N2348H variant (also known as c.7042A>C), located in coding exon 13 of the BRCA2 gene, results from an A to C substitution at nucleotide position 7042. The asparagine at codon 2348 is replaced by histidine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637661	SCV000759130	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2348 of the BRCA2 protein (p.Asn2348His). This variant is present in population databases (rs55742659, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422755). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 37922907). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731714	SCV001983746	uncertain significance	not specified	2021-09-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7042A>C (p.Asn2348His) 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 4e-06 in 250736 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7042A>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484747	SCV002774500	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	The BRCA2 c.7042A>C (p.Asn2348His) variant has been reported in the published literature in an individual with uterine corpus endometrial carcinoma (UCEC) (PMID: 29684080 (2018)). Additionally, it has been seen in a reportedly healthy individual who is over the age of 70 (FLOSSIES, https://whi.color.com/). A functional study using mouse models suggests this variant does not impact drug sensitivity or cell viability (PMID: 37922907 (2023), however further evidence is needed to assess the variant's impact on other BRCA2 related functions. The frequency of this variant in the general population, 0.000004 (1/250736 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.
Color Diagnostics, LLC DBA Color Health	RCV000509958	SCV004362187	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 2348 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). Functional studies have shown that this variant does not impact drug sensitivity or cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/250736 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV004003387	SCV004844353	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 2348 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). Functional studies have shown that this variant does not impact drug sensitivity or cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/250736 chromosomes 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.