13-32326148-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_000059.4(BRCA2):​c.473C>T​(p.Ser158Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S158T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

1
1
14
Splicing: ADA: 0.5123
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 1.71

Publications

15 publications found
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 Gene-Disease associations (from GenCC):
  • breast-ovarian cancer, familial, susceptibility to, 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
  • Fanconi anemia complementation group D1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
  • pancreatic cancer, susceptibility to, 2
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary breast ovarian cancer syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • medulloblastoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000059.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32326148-C-T is Pathogenic according to our data. Variant chr13-32326148-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51706.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BP4
Computational evidence support a benign effect (MetaRNN=0.21251321). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.473C>T p.Ser158Leu missense_variant, splice_region_variant Exon 5 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.473C>T p.Ser158Leu missense_variant, splice_region_variant Exon 5 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.104C>T p.Ser35Leu missense_variant, splice_region_variant Exon 5 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.473C>T splice_region_variant, non_coding_transcript_exon_variant Exon 4 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1456618
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
724878
African (AFR)
AF:
0.00
AC:
0
AN:
33338
American (AMR)
AF:
0.00
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39560
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86040
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5026
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1108258
Other (OTH)
AF:
0.00
AC:
0
AN:
60174
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Nov 07, 2023
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.S158L variant (also known as c.473C>T), located in coding exon 4 of the BRCA2 gene, results from a C to T substitution at nucleotide position 473. The serine at codon 158 is replaced by leucine, an amino acid with dissimilar properties. One study reports that this alteration was detected in a cohort of 176 women who underwent prophylactic bilateral mastectomies due to family history of breast cancer (Hartmann LC et al. J. Natl. Cancer Inst. 2001 Nov;93:1633-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Sanz DJ et al. Clin Cancer Res, 2010 Mar;16:1957-67). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 22, 2020
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 158 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. A mini-gene assay has shown that the variant causes the skipping of exon 5, which is expected to create a frameshift and premature translation stop signal (PMID: 20215541). However, this observation has not been confirmed in other types of RNA assays. This variant has been reported in at least one individual a family history of breast cancer (PMID: 11698567). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA2)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Familial cancer of breast Pathogenic:1
Aug 25, 2023
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1
Nov 21, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the BRCA2 protein (p.Ser158Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 11698567). ClinVar contains an entry for this variant (Variation ID: 51706). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown this missense change is associated with skipping of exon 5, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20215541, 27060066). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
0.99
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.58
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-0.90
T
PhyloP100
1.7
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.98
N;N
REVEL
Benign
0.18
Sift
Benign
0.066
T;T
Sift4G
Benign
0.48
T;T
Vest4
0.41
MutPred
0.39
Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);
MVP
0.82
MPC
0.021
ClinPred
0.17
T
GERP RS
4.1
gMVP
0.18
Mutation Taster
=83/17
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.51
dbscSNV1_RF
Benign
0.69
Splicevardb
3.0
SpliceAI score (max)
0.37
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.37
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs80358701; hg19: chr13-32900285; API