13-32344558-G-A

Position:

chr13-32344558-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):c.6842G>A(p.Gly2281Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000147 in 1,357,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.70

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:

BRCA2 (HGNC:):

BRCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.6842G>A	p.Gly2281Glu	missense_variant, splice_region_variant	12/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.6842G>A	p.Gly2281Glu	missense_variant, splice_region_variant	12/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.6473G>A	p.Gly2158Glu	missense_variant, splice_region_variant	12/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.6842G>A		splice_region_variant, non_coding_transcript_exon_variant	11/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

244980

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133142

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 SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1357750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

680324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.79e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000861

Hom.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2022	Observed in an individual with breast cancer (Deuitch et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7070G>A; Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32884827) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2024	The c.6842G>A variant (also known as p.G2281E) is located in coding exon 11 of the BRCA2 gene. The glycine at codon 2281 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. This alteration leads to increased but incomplete skipping of coding exon 11 (also known as exon 12 in the literature; Hujová P et al. Mol Biol Rep, 2019 Jun;46:2877-2884; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386; Ambry internal data). Complete loss of coding exon 11 retains nearly 50% homology-directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). However, the clinical impact of loss of exon 11 and to what extent exon 11 is lost is uncertain as a different variant that results in incomplete skipping of coding exon 11 was identified in a compound heterozygous state in a patient without apparent Fanconi Anemia (Li L et al. Hum Mutat, 2009 Nov;30:1543-50). This suggests that exon 11 skipping may be dispensable for clinically relevant function at an unknown threshold of loss (Li L et al. Hum Mutat, 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2019	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Nov 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). Not observed at significant frequency in large population cohorts (gnomAD). In silico analysis supports that this missense variant does not alter protein structure/function. Observed in an individual with breast cancer (Deuitch et al., 2020). This variant is associated with the following publications: (PMID: 32884827).ClinVar contains an entry for this variant (Variation ID: 926077). This nucleotide position is highly conserved . Studies have shown that this missense change results in the activation of a cryptic splice site (PMID: 32046981). 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 breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

Studies have shown that this missense change results in the activation of a cryptic splice site in 12 (PMID: 32046981). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 926077). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs80358908, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

0.44

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.49

MutPred

0.53

Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);

MVP

0.95

MPC

0.18

ClinPred

0.96

GERP RS

5.0

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.32

Position offset: 0

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