NM_000059.4:c.8187G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):c.8187G>T(p.Lys2729Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,614,138 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. K2729K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 6 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:2B:24O:1

Conservation

PhyloP100: 1.38

Variant links:

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]

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014209241).

BP6

Variant 13-32363389-G-T is Benign according to our data. Variant chr13-32363389-G-T is described in ClinVar as [Benign]. Clinvar id is 38142.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363389-G-T is described in Lovd as [Benign]. Variant chr13-32363389-G-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000453 (69/152274) while in subpopulation EAS AF= 0.00964 (50/5188). AF 95% confidence interval is 0.00751. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8187G>T	p.Lys2729Asn	missense_variant	Exon 18 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8187G>T	p.Lys2729Asn	missense_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7818G>T	p.Lys2606Asn	missense_variant	Exon 18 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*245G>T		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*245G>T		3_prime_UTR_variant	Exon 17 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00981

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000786

AC:

197

AN:

250698

Hom.:

AF XY:

0.000708

AC XY:

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00914

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000442

AC:

646

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

317

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0128

Gnomad4 SAS exome

AF:

0.00105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000453

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00964

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000558

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:2Benign:24Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:7

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000165. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01224 (Asian), derived from 1000 genomes (2012-04-30). -

Mar 14, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 21, 2014

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2019

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Molecular Endocrinology Laboratory, Christian Medical College

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:5Other:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys2729Asn variant in BRCA2 is classified as benign because it has been identified in 0.92% (183/19950) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 13, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1

Pathogenic:1Benign:1

Jul 26, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 10, 2019

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer

Benign:2

Feb 14, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 22, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 38142 as of 2024-12-05). -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys2729Asn variant is identified in the literature in at least 13 of 5204 proband chromosomes (frequency 0.002) in individuals with breast, ovarian, esophageal and hepatocelllar carcinoma, and in 7 of 1546 healthy control chromosomes (frequency 0.005); the elevated frequency in controls increases the likelihood that this variant is benign (Katagiri 1996, Zhi 2002, Hu 2004, Kawahara 2004, Ang 2007, Syamala 2007, Thirthagiri 2008, Lim 2009, Kaushal 2010, Akbari 2011). It is listed in the dbSNP database (ID# rs80359065) with a minor allele frequency of 0.003 (1000 genomes), also increasing the likelihood that this is a low frequency benign variant. Another variant at the same position, c.8187G>C, results in the same amino acid change and was reported in the UMD database in the presence of a second "pathogenic" variant, suggesting this variant may not have clinical significance. There was conflicting evidence in the literature as to the clinical significance of this variant. The p.Lys2729Asn variant was identified as co-occuring with a deleterious mutation, p.S2835X, in the BRCA2 gene in an acute myelogenous leukemia cell line from a Fanconi anemia patient (Howlett 2002, Ikeda 2003, Alter 2007). This suggests that the p.Lys2729Asn variant may play a role in this disorder whereby two BRCA2 mutations are required for disease progression, consistent with autosomal recessive inheritance. However, the p.Lys2729 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, leaning more towards pathognic, but this information is not predictive enough to assume pathogenicity. This variant has been reported to have 614:1 odds in favour of neutrality (Easton 2007) and a recent functional study suggests that it is a neutral variant (Farrugia 2008). In addition, Biswas et al. (2011) recently carried out functional studies to show it is neutral variant. Furthermore, Myriad genetics classifies this variant as a polymorphism (personal communication). In summary, based on the above information this variant is classified as Benign. -

Familial cancer of breast

Benign:1

Center for Precision Medicine, Meizhou People's Hospital

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.88

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

-0.11

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.49

MutPred

0.58

Loss of methylation at K2729 (P = 0.0308);Loss of methylation at K2729 (P = 0.0308);

MVP

0.92

MPC

0.17

ClinPred

0.066

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over