rs11571769

Positions:

• chr13-32379413-G-A
• chr13-32379413-G-C
• chr13-32379413-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.8851G>A​(p.Ala2951Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,613,810 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (96 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:44 O:1
• Conservation: PhyloP100: 7.91

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005076319).
• BP6: Variant 13-32379413-G-A is Benign according to our data. Variant chr13-32379413-G-A is described in ClinVar as [Benign]. Clinvar id is 41570.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379413-G-A is described in Lovd as [Benign]. Variant chr13-32379413-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00841 (1281/152290) while in subpopulation AMR AF= 0.0508 (777/15300). AF 95% confidence interval is 0.0478. There are 38 homozygotes in gnomad4. There are 724 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8851G>A	p.Ala2951Thr	missense_variant	22/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8851G>A	p.Ala2951Thr	missense_variant	22/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1270 AN: 152172 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00955 AC: 2395 AN: 250796 Hom.: 41 AF XY: 0.00886 AC XY: 1201 AN XY: 135576

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00677 AC: 9893 AN: 1461520 Hom.: 96 Cov.: 31 AF XY: 0.00681 AC XY: 4951 AN XY: 727048

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00574

Gnomad4 OTH exome AF: 0.00620

GnomAD4 genome AF: 0.00841 AC: 1281 AN: 152290 Hom.: 38 Cov.: 33 AF XY: 0.00972 AC XY: 724 AN XY: 74480

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00468 Hom.: 3

Bravo AF: 0.00992

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00563

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:44 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:13

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 28, 2016	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.036 (Admixed American/Latino), 0.0215 (South Asian), derived from 1000 genomes (2013-05-02). -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 14, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 29, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 25, 2022	The BRCA2 c.8851G>A variant is classified as Benign -

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 31, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.5% (402/11526) Latino chromosomes -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA2: PM5, BP4, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 13, 2017	- -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 04, 2014	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Malignant tumor of breast Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Ala2951Thr variant has been reported in our laboratory as well as in the literature in 36/5864 (0.006 frequency) proband chromosomes and in 1/1018 control chromosomes (0.001 frequency) (Bergthorsson_2001_11389159, Borg_2010_20104584, Saxena_2006_17018160, Lin_2003_12815053, Spitzer_2000_10699917, Serova-Sinilnikova_1997_9150172, Weber_2006_16685647, Wagner_1999_9971877, Waddell_2008_18497862). It is listed in dbSNP database (ID#:rs11571769) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. The p.Ala2951 residue is conserved across vertebrate species, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the p.Ala2951Thr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In one study, this variant did not co-segregate with cancer in three families, and its frequency in 4680 clinical samples was similar to that of the control population (Deffenbaugh_2002_12215251). Notably, this variant has been identified in the UMD database in a total of 15 individuals who had a second pathogenic variant (9 with BRCA2 mutations and 6 with BRCA1) and associated with a breast or ovarian cancer phenotype, increasing the likelihood that the p.Ala2951Thr variant does not have clinical significance. In addition, Myriad calls this variant as a polymorphism. In summary, based on the above information this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Center of Medical Genetics and Primary Health Care	-	- -

Ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 04, 2016

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 29, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BRCA2-related cancer predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0051	T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.51
MVP		0.89
MPC		0.16
ClinPred		0.020	T
GERP RS		5.6
gMVP		0.33

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: rs11571769; hg19: chr13-32953550; COSMIC: COSV66463542; COSMIC: COSV66463542;