13-32333247-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.1769T>G​(p.Phe590Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,611,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

4
8
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: 4.59
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 -1 ACMG points.

BP6
Variant 13-32333247-T-G is Benign according to our data. Variant chr13-32333247-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51189.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.1769T>G p.Phe590Cys missense_variant Exon 10 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.1769T>G p.Phe590Cys missense_variant Exon 10 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.1400T>G p.Phe467Cys missense_variant Exon 10 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.1769T>G non_coding_transcript_exon_variant Exon 9 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248932
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134758
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1459566
Hom.:
0
Cov.:
35
AF XY:
0.00000689
AC XY:
5
AN XY:
726122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152128
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
Sep 01, 2023
Department of Medical and Surgical Sciences, University of Bologna
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

BS3(Strong)+BP1(Strong)+BP5(Supporting) 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) -

Dec 11, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
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

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Apr 04, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 06, 2020
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. -

Sep 15, 2017
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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). -

not provided Uncertain:1Benign:1
Jul 25, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35402282 (2022), 34178674 (2021), 32854451 (2020)), and Cowden Syndrome/Cowden Syndrome-like Bannayan-Riley Ruvalcaba Syndrome (PMID: 29684080 (2018)). Published functional studies have reported that this variant does not have a deleterious effect on BRCA2 protein function (PMID: 29988080 (2018)). The frequency of this variant in the general population, 0.000012 (3/248932 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 26, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; A published in vitro functional assay suggests that this variant is able to rescue cell lethality (Mesman 2018); Observed in at least one individual with breast or ovarian cancer (Azzollini 2016); This variant is associated with the following publications: (PMID: 25348012, 11929857, 29988080, 24817641, 27062684, 32854451, 29684080) -

not specified Uncertain:1
Sep 28, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRCA2 c.1769T>G (p.Phe590Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244108 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1769T>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer who was indicated to carry another pathogenic variant, although the variant was not specified (Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in normal activity using multiple independent measures namely, complementation by BRCA2 variants of the cell lethal phenotype imposed by Cre-mediated loss of Brca2; HDR capacity, as measured by the repair of I-Sce1 induced double strand breaks (DSBs); and Cisplatin sensitivity of BRCA2 variants (Meman_2018). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer Uncertain:1
May 07, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Jan 07, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
26
DANN
Uncertain
0.99
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Benign
-1.2
T
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.22
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0070
D;D
Vest4
0.53
MutPred
0.51
Loss of MoRF binding (P = 0.0815);Loss of MoRF binding (P = 0.0815);
MVP
0.93
MPC
0.17
ClinPred
0.73
D
GERP RS
5.5
gMVP
0.58

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: rs80358459; hg19: chr13-32907384; API