rs398122716

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000059.4(BRCA2):c.8942A>G(p.Glu2981Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign 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. E2981K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 0.902

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 20 uncertain in NM_000059.4

BP4

Computational evidence support a benign effect (MetaRNN=0.16569051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8942A>G	p.Glu2981Gly	missense_variant	Exon 22 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.8942A>G	p.Glu2981Gly	missense_variant	Exon 22 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.8573A>G	p.Glu2858Gly	missense_variant	Exon 22 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.*1000A>G		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2 link	n.*1000A>G		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000242

AC:

AN:

248100

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460496

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.000113

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

85924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111654

Other (OTH)

AF:

0.00

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Apr 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with glycine at codon 2981 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least 2 families/individuals affected with hereditary breast and/or ovarian cancer and has been reported in 1 unaffected individual (PMID 24916970, 33471991, 34072659, 34287479). This variant has been identified in 6/248100 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. -

Feb 24, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 22, 2025

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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 provided

Uncertain:2

Oct 25, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 9170A>G; This variant is associated with the following publications: (PMID: 24916970, 22144684, 28480178, 32422573, 34072659, 34287479, 33471991, 12228710) -

not specified

Uncertain:1

Sep 18, 2023

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.8942A>G (p.Glu2981Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8942A>G has been reported in the literature in individuals affected with breast or ovarian cancer and an unaffected control (Peixoto_2014, Solano_2021, Nagy_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.5909C>A, p.Ser1970X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24916970, 34072659, 34287479, 33471991). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=1) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Jun 19, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

BRCA2-related cancer predisposition

Uncertain:1

May 24, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with glycine at codon 2981 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 performed for this variant. This variant has been reported in at least 2 families/individuals affected with hereditary breast and/or ovarian cancer and has been reported in 1 unaffected individual (PMID 24916970, 33471991, 34072659, 34287479). This variant has been identified in 6/248100 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. -

Familial cancer of breast

Uncertain:1

Jul 29, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Jan 21, 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

0.075

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.86

FATHMM_MKL

Uncertain

0.90

M_CAP

Benign

0.060

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.88

PhyloP100

0.90

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.27

Sift

Benign

0.13

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.32

MutPred

0.27

Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);

MVP

0.85

MPC

0.034

ClinPred

0.33

GERP RS

-1.5

gMVP

0.23

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over