13-32379429-A-C

Position:

chr13-32379429-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.8867A>C(p.Glu2956Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3

Conservation

PhyloP100: 2.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25593483).

BP6

Variant 13-32379429-A-C is Benign according to our data. Variant chr13-32379429-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38189.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.8867A>C	p.Glu2956Ala	missense_variant	22/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.8867A>C	p.Glu2956Ala	missense_variant	22/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250630

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135462

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461480

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2021	The BRCA2 c.8867A>C; p.Glu2956Ala variant (rs151174152), to our knowledge, is not reported in individuals in the medical literature but is reported in ClinVar (Variation ID: 38189). This variant is found on only three chromosomes (3/282024 alleles) in the Genome Aggregation Database. The glutamate at codon 2956 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.215). Given the lack of clinical and functional data, the significance of the p.Glu2956Ala variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 01, 2022	The frequency of this variant in the general population, 0.000011 (3/282024 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected study control individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer as well as in unaffected controls (PMID: 33471991); Also known as 9095A>C; This variant is associated with the following publications: (PMID: 28508593, 29179779, 29884841, 32377563, 33471991, 12228710) -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:1

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces glutamic acid with alanine at codon 2956 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 controls, showing inconclusive association with disease (OR=1.768, 95%CI 0.16 to 19.50; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007504). This variant has been identified in 3/282024 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	Counsyl	Nov 17, 2015	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 18, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2022	This missense variant replaces glutamic acid with alanine at codon 2956 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 controls, showing inconclusive association with disease (OR=1.768, 95%CI 0.16 to 19.50; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007504). This variant has been identified in 3/282024 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 breast ovarian cancer syndrome

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 24, 2018

Variant summary: BRCA2 c.8867A>C (p.Glu2956Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276410 control chromosomes (gnomAD). 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.8867A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2022

The BRCA2 c.8867A>C variant is predicted to result in the amino acid substitution p.Glu2956Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32953566-A-C), and in the ClinVar database with conflicting interpretations of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38189/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

0.16

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.91

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.47

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.040

D;D

Vest4

0.27

MVP

0.87

MPC

0.14

ClinPred

0.88

GERP RS

3.2

gMVP

0.43

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