rs80359189

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP3BP6

The NM_000059.4(BRCA2):c.9242T>C(p.Val3081Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,612,824 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. V3081F) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:11

Conservation

PhyloP100: 5.68

Publications

14 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 2 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 12 uncertain in NM_000059.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

BP6

Variant 13-32380131-T-C is Benign according to our data. Variant chr13-32380131-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38222.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9242T>C	p.Val3081Ala	missense_variant	Exon 24 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.9242T>C	p.Val3081Ala	missense_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8873T>C	p.Val2958Ala	missense_variant	Exon 24 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1300T>C		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1300T>C		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.00

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250360

AF XY:

0.0000222

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460624

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.0000225

AC:

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111654

Other (OTH)

AF:

0.0000332

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000349

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:1

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRCA2: BP1, BS3:Supporting -

Sep 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19043619, 25479140, 32123317, 25348012, 28283652, 10923033, 29394989, 28873162, 31131559, 30254663, 31131967, 29884841) -

not specified

Benign:3

Feb 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2024

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.9242T>C (p.Val3081Ala) results in a non-conservative amino acid change located in the OB3 fold (IPR015188) of 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 2e-05 in 347936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9242T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and related tumor phenotypes, it was also found in several healthy controls (Grant_2015, Shimelis_2017, Zuntini_2018, Al Hannan_2019). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8364G>A, p.Trp2788X; in UMD), providing supporting evidence for a benign role. An in vitro functional study reported that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (Guidugli_2018, Hart_2018). In addition, a recent multifactorial likelihood analysis predicted this variant to be Likely Benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 25479140, 28283652, 30254663, 29884841, 29394989, 31131967, 31131559). ClinVar contains an entry for this variant (Variation ID: 38222). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Apr 22, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 08, 2018

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. -

Jan 08, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS3, BP4, BP5_Strong c.9242T>C, located in exon 24 of the BRCA2 gene, knowing as a (potentially) clinically important functional domain, is predicted to result in the substitution of valine by alanine at codon 3081, p.(Val3081Ala). This variant is found in 3/267199 alleles at a frequency of 0.0011% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the BayesDel_noAF predictor score for this variant (0.107) suggests that it does not affect the protein function (BP4). It was reported by one calibrated study to affect protein function similar to benign control variants (PMID: 33609447) (BS3). This alteration was classified as a likely benign variant in a multifactorial likelihood analysis showing a Combined LR for clinical data indicative of strong evidence towards benign (LR 0.0139), based on co-segregation LR 1.8196, tumor pathology LR 0.89, co-occurrence LR 1.1293 and family history LR 0.774 (PMID: 31131967) (BP5_Strong). In addition, the variant was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (8x likely benign, 6x uncertain significance) and LOVD (4x uncertain significance). Based on the currently available information, c.9242T>C is classified as a benign variant according to ClinGen-BRCA2 Guidelines version v1.0.0. -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.9242T>C (p.Val3081Ala) missense change has a maximum subpopulation frequency of 0.0033% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/13-32954268-T-C). Seven of seven in silico tools predict a deleterious effect of this variant on protein function, however an in vitro functional study reported that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (BS3; PMID: 29394989). A large case control study of 41,890 European breast cancer patients and 41,607 European controls indicated that the variant is present in approximately equal proportions of cases and controls with an odds ratio of less than or equal to 1 (PMID: 28283652). This variant has been reported to co-occur with a pathogenic variant, BRCA2 c.8364G>A, p.Trp2788X (BP2; UMD database). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BS3, BP2. -

BRCA2-related disorder

Uncertain:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRCA2 c.9242T>C variant is predicted to result in the amino acid substitution p.Val3081Ala. This variant was reported as a variant of uncertain significance in an individual with breast cancer (Table 2, Al Hannan et al. 2019. PubMed ID: 31131559) and pancreatic cancer (Supplementary Table 1, Grant et al. 2015. PubMed ID:25479140). Functional studies have shown that this variant results in comparable activity to the wild type protein in homology-directed DNA repair (HDR) assays (Guindalini et al. 2022. PubMed ID: 35264596) and does not have an effect on splicing (Rowlands et al. 2021. PubMed ID: 34663891; Wai et al. 2020. PubMed ID: 32123317). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38222). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial prostate cancer

Benign:1

Mar 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

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

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Pathogenic

0.80

PhyloP100

5.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Vest4

0.58

MutPred

0.72

Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);

MVP

0.94

MPC

0.17

ClinPred

0.87

GERP RS

5.5

gMVP

0.46

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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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rs80359189

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