13-32333052-C-G

Position:

• chr13-32333052-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000059.4(BRCA2):​c.1574C>G​(p.Thr525Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T525I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.0740

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06337035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1574C>G	p.Thr525Ser	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1574C>G	p.Thr525Ser	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 245296 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000150

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456148 Hom.: 0 Cov.: 35 AF XY: 0.00000690 AC XY: 5 AN XY: 724208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000162

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 26, 2021	This missense variant replaces threonine with serine at codon 525 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, a different mutation leading to the same protein change has been reported in an individual affected with breast, ovarian or pancreatic cancer (PMID: 27882536). This variant has been identified in 5/245296 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. -
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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2022	The p.T525S variant (also known as c.1574C>G), located in coding exon 9 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1574. The threonine at codon 525 is replaced by serine, an amino acid with similar properties. This alteration was identified in a study of Mexican population data (Fern&aacute;ndez-Lopez JC et al. Hum Genomics, 2019 01;13:3). In addition, this alteration was identified in a female patient with colorectal cancer at age 46 (Ricker CN et al. Cancer, 2017 Oct;123:3732-3743) and in a cohort of women from Northeastern Mexico who had a personal and/or family history suggestive of hereditary breast cancer (Zayas-Villanueva OA et al. BMC Cancer, 2019 Jul;19:722). Another alteration (c.1573A>T) that results in the same amino acid change (p.T525S) was identified in 1/527 index patients with either breast, ovarian, or pancreatic cancer in Cyprus (Loizidou MA et al. Clin. Genet., 2017 Apr;91:611-615). This amino acid position is not 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Identified in patients with breast or colorectal cancer (Ricker et al., 2017; Zayas-Villanueva et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1802C>G; This variant is associated with the following publications: (PMID: 27882536, 28640387, 31331294, 30630528) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 25, 2023	In the published literature, this variant has been reported in individuals with a personal or family history of breast cancer (PMID: 31331294 (2019)), and colorectal cancer (PMID: 28640387 (2017)). The frequency of this variant in the general population, 0.00015 (5/33226 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 525 of the BRCA2 protein (p.Thr525Ser). This variant is present in population databases (rs397507271, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 252415). 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	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.0
DANN	Benign	0.49
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.26
Sift	Benign	0.11	T;T
Sift4G	Benign	0.35	T;T
Vest4		0.15
MutPred		0.15		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		0.57
MPC		0.022
ClinPred		0.020	T
GERP RS		-1.1
gMVP		0.070

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

Other links and lift over

dbSNP: rs397507271; hg19: chr13-32907189;