rs80359077

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM5PP3BP6

The NM_000059.4(BRCA2):c.8356G>A(p.Ala2786Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2786P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: 9.94

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 Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32370426-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

BP6

Variant 13-32370426-G-A is Benign according to our data. Variant chr13-32370426-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5}. Variant chr13-32370426-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8356G>A	p.Ala2786Thr	missense_variant	Exon 19 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.8356G>A	p.Ala2786Thr	missense_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7987G>A	p.Ala2663Thr	missense_variant	Exon 19 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*414G>A		non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*414G>A		3_prime_UTR_variant	Exon 18 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251430

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

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:

0.00000821

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 23, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3_supporting -

Mar 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 28222693 (2017), 27376475 (2016), 26689913 (2015), 14973102 (2004), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The variant has also been reported in unaffected individuals (PMID: 32467295 (2020), 28222693 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Published functional studies have reported conflicting results on the effect of this variant on BRCA2 protein function (PMID: 33314489 (2021), 29394989 (2018)). The frequency of this variant in the general population, 0.00075 (15/19954 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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. -

Nov 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8356G>A; p.Ala2786Thr variant (rs80359077), also known as 8584G>A for traditional nomenclature, is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Lai 2017, Suter 2004, Thirthagiri 2008, Wong 2015), but is also reported in healthy controls (Lai 2017). This variant is reported in ClinVar (Variation ID: 52560). It is found in the general East Asian population with an allele frequency of 0.08% (15/19954 alleles, including 1 homozygote) in the Genome Aggregation Database. The alanine at codon 2786 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lai KN et al. Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study. BMC Cancer. 2017 Feb 22;17(1):149. Suter NM et al. BRCA1 and BRCA2 mutations in women from Shanghai China. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):181-9. Thirthagiri E et al. Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. Breast Cancer Res. 2008;10(4):R59. Wong ES et al. Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population. PLoS One. 2015 Jul 29;10(7):e0134408. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:1

Feb 15, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2010

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 19, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Feb 09, 2023

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. -

Jun 10, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Benign:2

Aug 24, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.8356G>A (p.Ala2786Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251430 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00076 vs 0.00075), suggesting it might be a benign variant primarily in the populations of East Asian origin. c.8356G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (example, Kwong_2016, Schenkel_2016, Suter_2004, Thirthagiri_2008, Wong_2015), it is also reported in both breast cancer (BC) cases and in unaffected controls (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, no significant allelic differences of this variant have been identified in large-scale Asian case-control studies: i.e. the variant was similarly present in 10/7,840 BC cases and in 11/7,928 controls (P=0.85, Sullivan_2021). In another multi-ethnic Asian case-control study, the variant was also found insignificantly in both Breast Cancer (BC) cases and healthy controls: 8/2088 (0.17%) in BC cases and 4/1448 (0.28%) in healthy controls (P=0.5, Lai_2017). Additionally, at least one publication reports experimental evidence evaluating an impact on protein function. Assays measuring cellular viability and sensitivity to DNA damaging agents in a mouse embryonic stem cellbased model showed this variant produced the same effect as WT (Sullivan_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 26187060, 28222693, 27376475, 33314489, 14973102, 18627636, 26221963). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 06, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Malignant tumor of prostate

Uncertain:1

Jul 17, 2017

3DMed Clinical Laboratory Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.11

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Uncertain

0.61

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.011

D;D

Vest4

0.61

MutPred

0.75

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.93

MPC

0.16

ClinPred

0.59

GERP RS

4.3

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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