rs587782714

chr13-32339583-G-Achr13-32339583-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):c.5228G>A(p.Ser1743Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1743C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: -0.208

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07735893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5228G>A	p.Ser1743Asn	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5228G>A	p.Ser1743Asn	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 249568 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

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: 0.00000686 AC: 10 AN: 1458318 Hom.: 0 Cov.: 46 AF XY: 0.00000413 AC XY: 3 AN XY: 725552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2023	The p.S1743N variant (also known as c.5228G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5228. The serine at codon 1743 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in 1/157 individuals selected according to NCCN criteria for hereditary breast cancer and tested with a panel of 33 genes related to hereditary cancer (de Souza Timoteo AR et al. Breast Cancer Res. Treat., 2018 Dec;172:637-646). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is poorly 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. -
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). -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 24, 2016	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 09, 2023

Variant summary: BRCA2 c.5228G>A (p.Ser1743Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249568 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5228G>A has been reported in the literature in individuals affected with Breast Cancer (example, Guindalini_2022, deSouzaTimoteo_2018), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35264596, 30159786). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS=8, Likely benign=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The BRCA2 c.5228G>A variant is predicted to result in the amino acid substitution p.Ser1743Asn. This variant was reported as a variant of uncertain significance in a Brazilian breast cancer cohort study (de Souza Timoteo et al. 2018. PubMed ID: 30159786; Supp. Table 3 Guindalini RSC et al 2022. PubMed ID: 35264596). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32913720-G-A) and is listed in ClinVar as uncertain or likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/142783/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 16, 2023

The frequency of this variant in the general population, 0.0002 (7/34340 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an affected individual with breast cancer from Brazil (PMID: 30159786 (2018)). 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 31, 2024

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1743 of the BRCA2 protein (p.Ser1743Asn). This variant is present in population databases (rs587782714, gnomAD 0.02%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 30159786, 35264596). ClinVar contains an entry for this variant (Variation ID: 142783). 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	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.61
Dann	Benign	0.25
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.081	N
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.10
Sift	Benign	0.48	T;T
Sift4G	Benign	0.47	T;T
Vest4		0.25
MutPred		0.18		Loss of phosphorylation at S1743 (P = 0.0424);Loss of phosphorylation at S1743 (P = 0.0424);
MVP		0.83
MPC		0.021
ClinPred		0.015	T
GERP RS		1.3
gMVP		0.072

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: rs587782714; hg19: chr13-32913720;