rs80358732

chr13-32339451-A-Gchr13-32339451-A-T

Variant summary

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

The NM_000059.4(BRCA2):c.5096A>G(p.Asp1699Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,587,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1699N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1
• Conservation: PhyloP100: 3.16

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=0.08152783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5096A>G	p.Asp1699Gly	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5096A>G	p.Asp1699Gly	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 5 AN: 228402 Hom.: 0 AF XY: 0.0000242 AC XY: 3 AN XY: 123886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000702

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: 0.00000934

Gnomad OTH exome AF: 0.000369

GnomAD4 exome AF: 0.00000836 AC: 12 AN: 1434748 Hom.: 0 Cov.: 43 AF XY: 0.00000422 AC XY: 3 AN XY: 711648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000770

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: 0.00000363

Gnomad4 OTH exome AF: 0.0000846

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74486

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000831

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces aspartic acid with glycine at codon 1699 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 been reported in four individuals affected with breast cancer (PMID: 23192404, 27741520, 31780696; Leiden Open Variation Database DB-ID BRCA2_005779), and individuals with a personal or family history of BRCA2-related cancer (PMID: 36329109, 36977404). However, this variant is also located in a BRCA2 region without other clinically significant missense variants (PMID: 31911673). This variant has been identified in 5/228402 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 16, 2017	- -

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Observed in individuals with a personal and/or family history of breast, ovarian, or other cancers (Rummel et al., 2013; Lu et al., 2015; Fernandes et al., 2016; Palmero et al., 2016; Dutil et al., 2019; Guindalini et al., 2022; Matta et al.,, 2022; Villela et al., 2022; Carvalho et al., 2023); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5324A>G; This variant is associated with the following publications: (PMID: 10923033, 19912264, 23192404, 27741520, 27223485, 26689913, 31780696, 34884835, 36329109, 32377563, 29884841, 35264596, 36977404, Villela2022[preprint]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2023	The frequency of this variant in the general population, 0.000022 (5/228402 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 34884835 (2021), 31780696 (2019), 27741520 (2016), 23192404 (2013)), glioblastoma multiforme (PMID: 26689913 (2015)), or a family history of breast/ovarian cancer (PMID: 27223485 (2016)). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 26, 2015	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2023	The p.D1699G variant (also known as c.5096A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5096. The aspartic acid at codon 1699 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in Hispanic/Brazilian hereditary breast and/or ovarian cancer cohorts (Rummel S et al. Breast Cancer Res. Treat., 2013 Jan;137:119-25; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Palmero EI et al. Sci Rep, 2018 06;8:9188; Dutil J et al. Sci Rep, 2019 11;9:17769; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Carvalho CM et al. Rev Bras Ginecol Obstet, 2023 Feb;45:74-81). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2023	This missense variant replaces aspartic acid with glycine at codon 1699 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 been reported in four individuals affected with breast cancer (PMID: 23192404, 27741520, 31780696; Leiden Open Variation Database DB-ID BRCA2_005779), and individuals with a personal or family history of BRCA2-related cancer (PMID: 36329109, 36977404). However, this variant is also located in a BRCA2 region without other clinically significant missense variants (PMID: 31911673). This variant has been identified in 5/228402 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). -

Hereditary breast ovarian cancer syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1699 of the BRCA2 protein (p.Asp1699Gly). This variant is present in population databases (rs80358732, gnomAD 0.004%). This missense change has been observed in individual(s) with personal and/or family history of breast and ovarian cancer (PMID: 23192404, 27223485, 31780696). ClinVar contains an entry for this variant (Variation ID: 51765). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 16, 2022

Variant summary: BRCA2 c.5096A>G (p.Asp1699Gly) results in a non-conservative amino acid change located in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 228402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5096A>G has been reported in the literature in individuals affected with breast cancer (example, Rummel_2013, Fernandes_2016, Palmero_2015, Dutil_2019, Urbina-Jara_2021) and in a patient with glioblastoma multiforme (Lu_2015). These reports 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.2
Dann	Benign	0.85
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.33	N
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.15
Sift	Benign	0.24	T;T
Sift4G	Benign	0.46	T;T
Vest4		0.30
MVP		0.66
MPC		0.023
ClinPred		0.61	D
GERP RS		0.57
gMVP		0.18

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: rs80358732; hg19: chr13-32913588; COSMIC: COSV101204009;