chr13-32394782-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000059.4(BRCA2):c.9350A>G(p.His3117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. H3117Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.0230

Publications

8 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 3 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 31 uncertain in NM_000059.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30937266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9350A>G	p.His3117Arg	missense_variant	Exon 25 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.9350A>G	p.His3117Arg	missense_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8981A>G	p.His2994Arg	missense_variant	Exon 25 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1408A>G		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1408A>G		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251332

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.9350A>G (p.His3117Arg) variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251332 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with unspecified personal and family history who underwent hereditary cancer multigene panel (Li et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9578A>G; This variant is associated with the following publications: (PMID: 12228710, 32377563, 29884841, 31853058) -

not specified

Uncertain:1

Aug 21, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Nov 20, 2023

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 histidine with arginine at codon 3117 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to have a likelihood ratio for pathogenicity based on personal and family history of 0.3385 (PMID: 31853058). This variant has been identified in 1/251332 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Uncertain:1

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Feb 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 3117 of the BRCA2 protein (p.His3117Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome

Benign:1

May 15, 2025

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.11

CADD

Benign

4.4

(source)

DANN

Benign

0.91

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.026

M_CAP

Benign

0.064

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.95

PhyloP100

0.023

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.51

Sift

Benign

0.79

T;T

Sift4G

Benign

0.68

T;T

Vest4

0.47

MutPred

0.64

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.84

MPC

0.022

ClinPred

0.044

GERP RS

-2.5

gMVP

0.35

Mutation Taster

=75/25

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