rs276174886

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000059.4(BRCA2):c.6929C>A(p.Thr2310Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,411,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 3.04

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37071627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.6929C>A	p.Thr2310Asn	missense_variant	12/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.6929C>A	p.Thr2310Asn	missense_variant	12/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.6560C>A	p.Thr2187Asn	missense_variant	12/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.6929C>A		non_coding_transcript_exon_variant	11/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249990

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1411594

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

704996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000176

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000681

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 18, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2024	The p.T2310N variant (also known as c.6929C>A), located in coding exon 11 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6929. The threonine at codon 2310 is replaced by asparagine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Thirthagiri E et al. Breast Cancer Res., 2008 Jul;10:R59; Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196). In one study, functional analysis of this alteration indicates no effect on cell viability or sensitivity to DNA damaging agents (Sullivan T et al. Hum Mutat, 2021 Feb;42:200-212). Of note, this alteration is also known as 7157C>A in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Fanconi anemia complementation group D1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2015

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. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Aug 07, 2023

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 -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.89

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.34

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0070

D;D

Vest4

0.49

MutPred

0.19

Loss of phosphorylation at T2310 (P = 0.0059);Loss of phosphorylation at T2310 (P = 0.0059);

MVP

0.93

MPC

0.17

ClinPred

0.31

GERP RS

4.0

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over