rs11571657

chr13-32339995-T-G

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.5640T>G(p.Asn1880Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,612,424 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1880D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:28 O:1
• Conservation: PhyloP100: 0.100

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=0.0074713826).
• BP6: Variant 13-32339995-T-G is Benign according to our data. Variant chr13-32339995-T-G is described in ClinVar as [Benign]. Clinvar id is 51896.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339995-T-G is described in Lovd as [Benign]. Variant chr13-32339995-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00265 (404/152284) while in subpopulation AFR AF= 0.00931 (387/41576). AF 95% confidence interval is 0.00854. There are 2 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5640T>G	p.Asn1880Lys	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5640T>G	p.Asn1880Lys	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000771 AC: 192 AN: 249036 Hom.: 2 AF XY: 0.000535 AC XY: 72 AN XY: 134598

Gnomad AFR exome AF: 0.00927

Gnomad AMR exome AF: 0.00105

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: 0.0000177

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000294 AC: 429 AN: 1460140 Hom.: 3 Cov.: 43 AF XY: 0.000252 AC XY: 183 AN XY: 726230

Gnomad4 AFR exome AF: 0.00945

Gnomad4 AMR exome AF: 0.00103

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: 0.0000180

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152284 Hom.: 2 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74470

Gnomad4 AFR AF: 0.00931

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.00286

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:8

Benign, criteria provided, single submitter	literature only	Counsyl	May 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Asn1880Lys variant has been previously observed in 7/5248 (frequency: 0.001) proband chromosomes from individuals with a family history of breast and/or ovarian cancer (Borg 2010, Haffty 2009, Real 2002, Weitzel 2005). This individuals racial origin is reported to be of African American ancestry and of the individuals reported in the literature with the p.Asn1880Lys variant, 3 were reported of African American descent. In addition, in the Exome Variant Server this variant was not found in any of the 8,600 Caucasian control chromosomes, but was found in 41/4365 (frequency: 0.009) African American control chromosomes increasing the likelihood that this variant is a benign polymorphism in this population of origin. It should also be noted that this lab has sequenced the BRCA2 gene in a limited number of African American individuals such that the full spectrum of benign variation has not yet been defined for this population, and increasing the possibility that this may be a benign variant. Future analysis could reveal that the p.Asn1880Lys variant is common in this population and therefore unlikely to be of clinical significance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs11571657) with a global minor allele frequency (MAF) of 0.002 (1000 Genomes) further lending to a benign role for this variant. Finally, this residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, further leaning to a benign role for this variant. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in this individual, but based on the above information this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00909 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13). -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 01, 2008	- -

not specified Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 28, 2022	The p.Asn1880Lys variant in BRCA2 is classified as benign because it has been identified in 0.92% (229/24894, 2 homozygotes) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as benign on Jun 18, 2019 by the ClinGen-approved ENIGMA expert panel (Variation ID 51896). ACMG/AMP Criteria applied: BA1. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Dec 17, 2015	- -
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	Jul 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2018	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 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	Nov 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Hereditary breast ovarian cancer syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	BRCA2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2018	This variant is associated with the following publications: (PMID: 21520273, 25637381, 11241844, 27884173, 26332594, 24728327, 11950811, 12624724, 9971877, 20104584, 19491284, 16030099, 22034289, 18724707, 12491487, 27741520) -

Breast and/or ovarian cancer Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 27, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	May 08, 2012	- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 25, 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. -

Breast neoplasm Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	9.2
Dann	Benign	0.97
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.24	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.029	D;D
Vest4		0.29
MutPred		0.67		Loss of ubiquitination at K1875 (P = 0.0272);Loss of ubiquitination at K1875 (P = 0.0272);
MVP		0.83
MPC		0.033
ClinPred		0.021	T
GERP RS		1.8
gMVP		0.097

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: rs11571657; hg19: chr13-32914132;