Submissions for variant NM_000059.4(BRCA2):c.6929C>A (p.Thr2310Asn)

gnomAD frequency: 0.00003  dbSNP: rs276174886

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487181	SCV000566740	uncertain significance	not provided	2015-05-28	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6929C>A at the cDNA level, p.Thr2310Asn (T2310N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant, also published as BRCA2 7157C>A using alternate nomenclature, has been reported in at least one individual of Indian ethnicity with a personal and/or family history of breast or ovarian cancer (Thirthagiri 2008). BRCA2 Thr2310Asn 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 Threonine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Thr2310Asn occurs at a position that is conserved in mammals and is not located in a known functional domain (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Thr2310Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563131	SCV000666091	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	The c.6929C>A (p.T2310N) alteration is located in exon 12 (coding exon 11) of the BRCA2 gene. This alteration results from a C to A substitution at nucleotide position 6929, causing the threonine (T) at amino acid position 2310 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000563131	SCV000683828	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 2310 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). A functional study has shown that this variant does not impact cell viability or sensitivity to DNA damaging agents (PMID: 33314489). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 18627636, 29470806, 33314489). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008541). This variant has been identified in 7/249990 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.
Invitae	RCV001322299	SCV001513164	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2310 of the BRCA2 protein (p.Thr2310Asn). This variant is present in population databases (rs276174886, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18627636, 29470806). ClinVar contains an entry for this variant (Variation ID: 52219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Genetics and Molecular Pathology, SA Pathology	RCV000113672	SCV002761628	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-11-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003319303	SCV004023361	uncertain significance	Familial cancer of breast	2023-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2310 of the BRCA2 protein (p.Thr2310Asn). This variant is present in population databases (rs276174886, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18627636, 29470806). ClinVar contains an entry for this variant (Variation ID: 52219) classified as uncertain significance . This amino acid position is well moderately conserved (PhyloP=3.19).In addition, this alteration is predicted to be tolerated by in silico analysis. 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
Neuberg Centre For Genomic Medicine, NCGM	RCV003338397	SCV004047318	uncertain significance	Fanconi anemia complementation group D1		criteria provided, single submitter	clinical testing	The missense variant c.6929C>A (p.Thr2310Asn) in BRCA2 gene has been observed in several individuals affected with breast and/or ovarian cancer (Singh J et al., 2018). This variant is reported with the allele frequency (0.0028%) in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Uncertain significance. The amino acid Thr at position 2310 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr2310Asn in BRCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Neuberg Centre For Genomic Medicine, NCGM	RCV000113672	SCV004100430	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	The missense variant p.T2310N in BRCA2 (NM_000059.4) has been reported in patients affected with breast and ovarian cancer ( Singh J et al, Thirthagiri E et al). The missense variant c.6929C>A (p.T2310N) in BRCA2 (NM_000059.4) is observed in 6/30556 (0.0196%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state.It has been submitted to ClinVar as Uncertain Significance. The p.T2310N missense variant are contradictory in their predictions (SIFT-Tolerated, Polyphen-2-Damaging). The nucleotide c.6929 in BRCA2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000113672	SCV004844330	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 2310 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). A functional study has shown that this variant does not impact cell viability or sensitivity to DNA damaging agents (PMID: 33314489). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 18627636, 29470806, 33314489). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008541). This variant has been identified in 7/249990 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113672	SCV000146970	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing