chr13-32379882-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):c.9086C>T(p.Ala3029Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,302 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3029A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:3

Conservation

PhyloP100: 3.64

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 -1 ACMG points.

BP6

Variant 13-32379882-C-T is Benign according to our data. Variant chr13-32379882-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52744.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9086C>T	p.Ala3029Val	missense_variant	Exon 23 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.9086C>T	p.Ala3029Val	missense_variant	Exon 23 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8717C>T	p.Ala2906Val	missense_variant	Exon 23 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1144C>T		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*1144C>T		3_prime_UTR_variant	Exon 22 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249594

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461302

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:5

Feb 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2007

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2001

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3029 of the BRCA2 protein (p.Ala3029Val). This variant is present in population databases (rs80359162, gnomAD 0.02%). This variant has been reported in an individual affected with breast cancer and another individual affected with leukemia (PMID: 31102422, 33471991; Leiden Open Variation Database DB-ID BRCA2_000401). Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. (Variation ID: 52744) . A functional study has reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 29884841).in-silico tools predict a damaging effect of the variant on protein function.. 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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2Benign:1

Nov 27, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.9086C>T at the cDNA level, p.Ala3029Val (A3029V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 9314C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ala3029Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala3029Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Jul 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9086C>T; p.Ala3029Val variant (rs80359162, ClinVar Variation ID: 52744) is reported in the literature in an individual affected with acute lymphoblastic leukemia (de Smith 2019). This variant is found in the Admixed American population with an allele frequency of 0.02% (7/34,468 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses (SpliceAI: 0.3) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional analyses of the variant protein using a homology directed repair assay show a neutral effect (Hart 2019, Hu 2022, Richardson 2021). Due to limited information, the clinical significance of this variant is uncertain at this time. References: de Smith AJ et al. Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children. Genes Chromosomes Cancer. 2019 Oct;58(10):723-730. PMID: 31102422. Hart SN et al. Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med. 2019 Jan;21(1):71-80. PMID: 29884841. Hu C et al. Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. Clin Cancer Res. 2022 Sep 1;28(17):3742-3751. PMID: 35736817. Richardson ME et al. Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. Am J Hum Genet. 2021 Mar 4;108(3):458-468. PMID: 33609447. -

Nov 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jul 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with valine at codon 3029 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 reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29884841, 35736817). This variant has been reported in an individual affected with breast cancer and another individual affected with leukemia (PMID: 31102422, 33471991; Leiden Open Variation Database DB-ID BRCA2_000401).This variant has been identified in 8/249594 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. -

Dec 06, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Uncertain:1

Sep 23, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9086C>T (p.Ala3029Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249594 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9086C>T has been reported in the literature without strong evidence for or against pathogenicity (Karchin_2008, de Smith_2016). In a cell-based homology directed DNA repair activity assay, this variant was found to have neutral effect (Hart_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly benign. -

BRCA2-related cancer predisposition

Uncertain:1

Mar 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2-related disorder

Uncertain:1

Jun 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9086C>T variant is predicted to result in the amino acid substitution p.Ala3029Val. This variant has been reported in an individual with acute lymphoblastic leukemia (Table S1, de Smith et al. 2019. PubMed ID: 31102422). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954019-C-T). IT is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Nov 19, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3029 of the BRCA2 protein (p.Ala3029Val). This variant is present in population databases (rs80359162, gnomAD 0.02%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 31102422). ClinVar contains an entry for this variant (Variation ID: 52744). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Breast and/or ovarian cancer

Benign:1

Dec 08, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.0028

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.070

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.29

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.59

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.034

D;D

Vest4

0.36

MutPred

0.25

Loss of disorder (P = 0.0534);Loss of disorder (P = 0.0534);

MVP

0.89

MPC

0.023

ClinPred

0.27

GERP RS

4.8

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: 31

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