rs80358731

chr13-32339450-G-Achr13-32339450-G-Cchr13-32339450-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):c.5095G>A(p.Asp1699Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,587,408 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1699G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 0.00200

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00714007).
• BP6: Variant 13-32339450-G-A is Benign according to our data. Variant chr13-32339450-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 37946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5095G>A	p.Asp1699Asn	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5095G>A	p.Asp1699Asn	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152116 Hom.: 1 Cov.: 33

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: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000427 AC: 98 AN: 229434 Hom.: 0 AF XY: 0.000611 AC XY: 76 AN XY: 124438

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: 0.00379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000258 AC: 370 AN: 1435174 Hom.: 4 Cov.: 43 AF XY: 0.000384 AC XY: 273 AN XY: 711808

Gnomad4 AFR exome AF: 0.0000623

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.000304

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000492 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000528 AC: 64

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 05, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
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	Nov 20, 2023	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Asp1699Asn variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), GeneInsight COGR, COSMIC, MutDB, ARUP laboratories or LOVD databases. The p.Asp1699Asn variant was identified in dbSNP (ID: rs80358731 “With other allele”, with a minor allele frequency of 0.0006 (3 of 5000 chromosomes in1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13th, 2015) in 64 of 118544 chromosomes (frequency: 0.0005399) or 62 of 15484 alleles from a population of South Asians with 1 homozygous, 2 of 884 alleles of other populations and was not found in European (Non-Finnish), East Asian, African, Latino, European (Finnish) and individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified by our laboratory in 2 individuals with ovarian and breast cancers. The ClinVar database had conflicting interpretations: classified as a likely benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), by Invitae and Ambry Genetics whereas BIC classified the variant as uncertain significance. The BRCA Share UMD database classified the variant as unknown. In-silico splicing predictors do not predict any difference in splicing. The p.Asp1699 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant amino acid Asparagine (Asn) is present in Cows, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as Likely Benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2020	This variant is associated with the following publications: (PMID: 19912264, 22752604, 28692054, 26580448, 30555256, 31131967) -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 13, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2019	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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2018	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.7
Dann	Uncertain	0.98
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.052	N
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.094
Sift	Benign	0.24	T;T
Sift4G	Benign	0.64	T;T
Vest4		0.23
MutPred		0.53		Gain of MoRF binding (P = 0.0924);Gain of MoRF binding (P = 0.0924);
MVP		0.77
MPC		0.022
ClinPred		0.037	T
GERP RS		3.1
gMVP		0.074

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: rs80358731; hg19: chr13-32913587;