rs80358874

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000059.4(BRCA2):​c.6338A>G​(p.Asn2113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,608,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
15

Clinical Significance

Benign reviewed by expert panel U:3B:15

Conservation

PhyloP100: -1.03
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 -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.018149316).
BP6
Variant 13-32340693-A-G is Benign according to our data. Variant chr13-32340693-A-G is described in ClinVar as [Benign]. Clinvar id is 38039.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340693-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.6338A>G p.Asn2113Ser 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.6338A>G p.Asn2113Ser missense_variant Exon 11 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.5969A>G p.Asn1990Ser missense_variant Exon 11 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.6338A>G non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000118
AC:
29
AN:
244836
Hom.:
0
AF XY:
0.000166
AC XY:
22
AN XY:
132490
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000181
Gnomad ASJ exome
AF:
0.00164
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000447
Gnomad OTH exome
AF:
0.000338
GnomAD4 exome
AF:
0.0000563
AC:
82
AN:
1456562
Hom.:
0
Cov.:
46
AF XY:
0.0000607
AC XY:
44
AN XY:
724400
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000208
Gnomad4 ASJ exome
AF:
0.00189
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000183
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000205
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Benign
Submissions summary: Uncertain:3Benign:15
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:3
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 = 0.0000000000117 -

Mar 08, 2006
Sharing Clinical Reports Project (SCRP)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 14, 2014
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

not provided Uncertain:1Benign:3
Jan 30, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The BRCA2 c.6338A>G (p.Asn2113Ser) variant involves the alteration of a non-conserved nucleotide, which 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/119730 (1/14662), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals that have also classified the variant as "benign/neutral." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. In addition, BRCAshare, a reputable database that incorporates LCA samples indicates the variant co-occurred with another pathogenic BRCA2 variant, c.5576_5579delTTA in 3 individuals, along with an internal LCA sample reports the variant to co-occur with a BRCA1 pathogenic variant, c.68_29delAG. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA2: BP4, BS2 -

Jun 27, 2017
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Hereditary cancer-predisposing syndrome Benign:3
Apr 21, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

Apr 04, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

not specified Benign:2
Oct 30, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

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

- -

Hereditary breast ovarian cancer syndrome Benign:2
Mar 30, 2023
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Feb 03, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1
-
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.Asn2113Ser variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs80358874) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and two other submitters; as likely benign by four submitters; as uncertain significance by three submitters), MutDB, LOVD 3.0 (5x), UMD-LSDB (6x as likely neutral), BIC Database (13x), and in ARUP Laboratories (not pathogenic or of no clinical significance) databases. The variant was not identified in COGR, Cosmic, or the Zhejiang University Database. The variant was identified in control databases in 30 of 271298 chromosomes 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: Other in 3 of 6322 chromosomes (freq: 0.0005), Latino in 6 of 33104 chromosomes (freq: 0.0002), European in 5 of 124988 chromosomes (freq: 0.00004), Ashkenazi Jewish in 16 of 9828 chromosomes (freq: 0.002), while the variant was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Asn2113 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 addition, a systematic genetic assessment and multifactorial probability based model identified the variant has odds in favor of neutrality 1749 and posterior probability of being deleterious 1.17√ó10-11 (Easton 2007, Lindor 2012). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
0.035
DANN
Benign
0.59
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.063
N
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.018
T;T
MetaSVM
Benign
-0.90
T
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.11
N;N
REVEL
Benign
0.099
Sift
Uncertain
0.028
D;D
Sift4G
Benign
0.35
T;T
Vest4
0.19
MVP
0.62
MPC
0.019
ClinPred
0.037
T
GERP RS
0.28
gMVP
0.10

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: rs80358874; hg19: chr13-32914830; API