rs587781485

Positions:

• chr13-32357754-G-A
• chr13-32357754-G-C
• chr13-32357754-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

The NM_000059.4(BRCA2):​c.7630G>A​(p.Gly2544Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G2544G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• BP6: Variant 13-32357754-G-A is Benign according to our data. Variant chr13-32357754-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141088.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7630G>A	p.Gly2544Ser	missense_variant	16/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7630G>A	p.Gly2544Ser	missense_variant	16/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33609447, 32377563) -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2017	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	Variant summary: BRCA2 c.7630G>A (p.Gly2544Ser) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7630G>A has been reported to co-occur with another pathogenic variant in BRCA1 (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161PhefsX3) in a clinical sample in the literature (example: Schenk_2017) as well as in one internal sample, providing supporting evidence for its benign role. The literature report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In Homology-directed repair (HDR) activity, the variant was found to be functional (Richardson_2021, Hu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32377563, 35736817, 33609447, 28704513). Nine other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 30, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 27, 2017

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2544 of the BRCA2 protein (p.Gly2544Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141088). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33609447). 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2020

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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.73
MutPred		0.85		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.95
MPC		0.17
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs587781485; hg19: chr13-32931891;