13-32363389-G-T

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

6
9

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]

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
BRCA2NM_000059.4 linkc.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 Appris UniProt
BRCA2ENST00000380152.8 linkc.8187G>T p.Lys2729Asn missense_variant Exon 18 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.7818G>T p.Lys2606Asn missense_variant Exon 18 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*245G>T non_coding_transcript_exon_variant Exon 17 of 26 2 ENSP00000506251.1 A0A7P0TAP7
BRCA2ENST00000614259 linkn.*245G>T 3_prime_UTR_variant Exon 17 of 25 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000460
AC:
70
AN:
152156
Hom.:
0
Cov.:
32
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.:
0
AF XY:
0.000708
AC XY:
96
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.:
6
Cov.:
31
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:
69
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000631
AC XY:
47
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.:
1
Bravo
AF:
0.000555
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000824
AC:
100
Asia WGS
AF:
0.00606
AC:
21
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

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. -

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
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
19
DANN
Benign
0.97
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.88
D
MetaRNN
Benign
0.014
T;T
MetaSVM
Uncertain
-0.11
T
PrimateAI
Benign
0.33
T
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
T
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.

Other links and lift over

dbSNP: rs80359065; hg19: chr13-32937526; COSMIC: COSV66448828; COSMIC: COSV66448828; API