Variant rs80358945 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000059.4(BRCA2):c.7177A>G(p.Met2393Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2393T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.85

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:

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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	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7177A>G	p.Met2393Val	missense_variant	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7177A>G	p.Met2393Val	missense_variant	14/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251284

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135812

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 27, 2009	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Oct 29, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 16, 2023	This missense variant replaces methionine with valine at codon 2393 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). Splice site prediction tools suggest that this variant may impact RNA splicing by the creation of a new donor site, however this effect on splicing appears to affect less than 5% of transcripts (PMID 31191615). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0499 and 0.4781, respectively (PMID: 31131967). This variant has been identified in 2/251284 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2023	The p.M2393V variant (also known as c.7177A>G), located in coding exon 13 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7177. The methionine at codon 2393 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. This alteration has been shown to result in low-level aberrant RNA splicing (Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503). RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In addition, this alteration is predicted to be tolerated by protein in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 01, 2023	This missense variant replaces methionine with valine at codon 2393 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). Splice site prediction tools suggest that this variant may impact RNA splicing by the creation of a new donor site, however this effect on splicing appears to affect less than 5% of transcripts (PMID 31191615). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0499 and 0.4781, respectively (PMID: 31131967). This variant has been identified in 2/251284 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing; Published minigene assay demonstrated this variant to have a weak impact on splicing resulting in about 5% aberrant transcript; however, the predominant transcript produced was full-length (Fraile-Bethencourt et al., 2019); Observed in an individual with breast cancer and a family history of breast and/or ovarian cancer (Lu et al., 2012); Also known as 7405A>G; This variant is associated with the following publications: (PMID: 21523855, 31191615, 22476429) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2393 of the BRCA2 protein (p.Met2393Val). This variant is present in population databases (rs80358945, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52277). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.19

CADD

Benign

8.8

DANN

Benign

0.35

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.26

M_CAP

Benign

0.043

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.65

N;N

REVEL

Uncertain

0.40

Sift

Benign

1.0

T;T

Sift4G

Benign

0.89

T;T

Vest4

0.20

MutPred

0.21

Gain of methylation at K2392 (P = 0.021);Gain of methylation at K2392 (P = 0.021);

MVP

0.82

MPC

0.020

ClinPred

0.025

GERP RS

2.7

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.46

Position offset: -1

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