chr13-32339990-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000059.4(BRCA2):​c.5635G>A​(p.Glu1879Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

3
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:21

Conservation

PhyloP100: 0.477
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.060434014).
BP6
Variant 13-32339990-G-A is Benign according to our data. Variant chr13-32339990-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51895.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=9}. Variant chr13-32339990-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.5635G>A p.Glu1879Lys missense_variant Exon 11 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.5635G>A p.Glu1879Lys missense_variant Exon 11 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.5266G>A p.Glu1756Lys missense_variant Exon 11 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.5635G>A non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000132
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000133
AC:
33
AN:
248816
Hom.:
0
AF XY:
0.000171
AC XY:
23
AN XY:
134454
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000168
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000239
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000904
AC:
132
AN:
1459830
Hom.:
1
Cov.:
44
AF XY:
0.000102
AC XY:
74
AN XY:
726032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000675
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000152
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000963
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152222
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000124
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000214
AC:
26
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:21
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:7
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRCA2 p.Glu1879Lys variant was identified in 3 of 4882 proband chromosomes (frequency: 0.0006) from Malaysian and American individuals or families with breast or endometrial cancer (Thirthagiri 2008, Pennington 2012, Borg 2010). The variant was also identified in dbSNP (ID: rs55996097) “With Pathogenic, other allele”, ClinVar (conflicting interpretations of pathogenicity: classified as benign by Invitae and SCRP; classified as likely benign by Ambry Genetics, GeneDx, Illumina Clinical Services Laboratory, and two other clinical laboratories; and classified as uncertain significance by BIC, Integrated Genetics/Laboratory Corporation of America, CHEO and Quest Diagnostics Nichols Institute San Juan Capistrano), GeneInsight-COGR (1x), LOVD 3.0 (1x), UMD-LSDB (classified as 3-UV, co-occurring with the pathogenic variant BRCA2 c.8643dup, p.Ile2822Tyrfs*23) and BIC Database (10x, clinical importance unknown, classification pending). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 35 of 274724 chromosomes (1 homozygous) at a frequency of 0.0001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 28 of 125750 chromosomes (freq: 0.0002), and South Asian in 7 (1 homozygous) of 29948 chromosomes (freq: 0.0002), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1879 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 occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

May 29, 2002
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
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. -

Sep 01, 2023
Department of Medical and Surgical Sciences, University of Bologna
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

BS1(Strong)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Aug 24, 2009
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 02, 2020
BRCAlab, Lund University
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:4
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 10, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32426482, 27062684, 28222693, 28263838, 18092194, 24504028, 26689913, 23555315, 20104584, 18627636, 22811390, 16847550, 16760289) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 06, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Glu1879Lys variant has been reported in individuals with breast and/or ovarian cancer; however, inheritance and specific clinical information were not reported (Borg 2010, Pennington 2012, and Thirthagiri 2008). The p.Glu1879Lys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the South Asian population (identified in 7 out of 29,948 chromosomes; 1 homozygote), and is classified as likely benign/benign in ClinVar (Variant ID: 51895). The glutamic acid at codon 1,879 is moderately conserved considering 12 species (Alamut software v2.9.0), and it is a lysine in dogs, suggesting that this change may be evolutionary tolerated. Computational analyses predict that this variant does not affect the BRCA2 protein structure/function (GV/GD: C0, SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Based on the available evidence, the p.Glu1879Lys variant is classified as likely benign. -

Mar 19, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Dec 28, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

May 06, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Sep 08, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:3
Feb 16, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRCA2 c.5635G>A (p.Glu1879Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248816 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer allowing no conclusion about variant significance. c.5635G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer, contralateral breast cancer, and other cancerous settings ((example, Borg_2010, Capalbo_2006, Capanu_2011, Cunningham_2014, Giannini_2006, Haiman_2013, Pennington_2013, Seymour_2008, Thirthagiri_2008, Azzolini_2016, Lai_2017, Zuntini_2018). The variant was reported as not co-segregating with disease in at-least one of these reports (Zuntini_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants in the BRCA2 and BRCA1 genes have been reported in the UMD and the BIC databases respectively in addition to another co-occurrence in the MSH6 gene tested at our laboratory (BRCA2 c.8463dup, p.Ile2822fs; BRCA1 c.5263_5264insC, p.Ser1755?fs, MSH6 c.3733_3739dupTTTTCAA , p.Thr1247fsX30), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some of these submitters cite overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=6). Based on the evidence outlined above, the variant was re-classified from likely benign to benign. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 27, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Benign:1
Apr 27, 2017
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). 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 disorder Benign:1
Dec 04, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
5.7
DANN
Uncertain
0.97
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.13
N
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.060
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Uncertain
0.34
Sift
Benign
0.41
T;T
Sift4G
Benign
0.46
T;T
Vest4
0.31
MVP
0.83
MPC
0.023
ClinPred
0.023
T
GERP RS
3.0
gMVP
0.23

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: rs55996097; hg19: chr13-32914127; COSMIC: COSV99061600; API