rs276174923

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000059.4(BRCA2):c.9344A>G(p.Lys3115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 2.45

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32952166).

BP6

Variant 13-32394776-A-G is Benign according to our data. Variant chr13-32394776-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52817.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9344A>G	p.Lys3115Arg	missense_variant	25/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.9344A>G	p.Lys3115Arg	missense_variant	25/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8975A>G	p.Lys2992Arg	missense_variant	25/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1402A>G		non_coding_transcript_exon_variant	24/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1402A>G		3_prime_UTR_variant	24/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251298

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 13, 2024	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 18, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 25, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 21, 2015	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 9572A>G; This variant is associated with the following publications: (PMID: 10923033, 31843900, 12228710) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2023	The frequency of this variant in the general population, 0.00029 (9/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported have no effect on BRCA2 mRNA splicing (PMID: 31843900 (2019)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (PMID: 33471991 (2021), ). 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 3115 of the BRCA2 protein (p.Lys3115Arg). This variant is present in population databases (rs276174923, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 33314489). ClinVar contains an entry for this variant (Variation ID: 52817). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33314489). 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. -

not specified

Uncertain:1Benign:1

Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2023	Variant summary: BRCA2 c.9344A>G (p.Lys3115Arg) results in a conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.9344A>G has been reported in the literature in individuals affected with breast cancer (example, Lai_2017, Sharma-Oates_2018, Casadei_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Sullivan_2021). The most pronounced variant effect results in approximately >50%-90% of normal activity and the authors concluding a neutral outcome based on 1. functionally indistinguishable from WT-BRCA2 in the mESC functional assay; 2. fully rescued the lethality of BRCA2-null-mESCs and 3. exhibited no sensitivity to 6 different DNA damaging agents. The following publications have been ascertained in the context of this evaluation (PMID: 31843900, 28222693, 35693198, 33314489). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This missense variant replaces lysine with arginine at codon 3115 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 shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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. -

BRCA2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 17, 2024

This missense variant replaces lysine with arginine at codon 3115 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 shown this variant was able to rescue Brca2-deficient mouse embryonic stem cells in sensitivity assays to DNA damaging agents (PMID: 33314489). This variant has been reported in one individual affected with breast cancer and two unaffected individuals (PMID: 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007522). This variant has been identified in 10/251298 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.099

Eigen_PC

Benign

0.000041

FATHMM_MKL

Uncertain

0.76

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.31

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.82

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.065

T;T

Sift4G

Benign

0.11

T;T

Vest4

0.47

MutPred

0.56

Loss of ubiquitination at K3115 (P = 0.0167);Loss of ubiquitination at K3115 (P = 0.0167);

MVP

0.91

MPC

0.030

ClinPred

0.14

GERP RS

4.7

gMVP

0.32

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

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