13-32332905-C-G

Position:

chr13-32332905-C-G

Variant summary

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

The NM_000059.4(BRCA2):c.1427C>G(p.Ser476Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,609,856 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: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

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:

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=0.30353266).

BP6

Variant 13-32332905-C-G is Benign according to our data. Variant chr13-32332905-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1427C>G	p.Ser476Cys	missense_variant	10/27	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.1427C>G	p.Ser476Cys	missense_variant	10/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.1058C>G	p.Ser353Cys	missense_variant	10/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.1427C>G		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

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

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246602

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133298

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

1457682

Hom.:

Cov.:

AF XY:

0.0000524

AC XY:

AN XY:

724892

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000657

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000187

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

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

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 25, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 16, 2001	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2023	The p.S476C variant (also known as c.1427C>G), located in coding exon 9 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1427. The serine at codon 476 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by 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	curation	Sema4, Sema4	Aug 25, 2021	- -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 21, 2016	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2024	Observed in an individual with acute myeloid leukemia (PMID: 26689913); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 1655C>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 33471991, 31131967, 31853058, 26689913) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The c.1427C>G (p.Ser476Cys) in BRCA2 gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is absent from the control population dataset of ExAC and has not, to our knowledge, been reported in HBOC individuals via published reports. It has been reported as VUS by several reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 14, 2022	The frequency of this variant in the general population, 0.0000072 (2/277996 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in an individual with acute myeloid leukemia (PMID: 26689913 (2015)), in individuals with breast cancer and in unaffected controls (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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 13, 2018

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 476 of the BRCA2 protein (p.Ser476Cys). This variant is present in population databases (rs80358431, gnomAD 0.002%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 10923033, 26689913). ClinVar contains an entry for this variant (Variation ID: 37739). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

0.060

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.47

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.044

D;D

Vest4

0.43

MutPred

0.24

Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);

MVP

0.91

MPC

0.15

ClinPred

0.39

GERP RS

5.3

gMVP

0.13

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