chr13-32319289-C-T
Position:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6
The NM_000059.4(BRCA2):c.280C>T(p.Pro94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P94T) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
4
12
Clinical Significance
Conservation
PhyloP100: 2.03
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.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 14 uncertain in NM_000059.4
BP4
Computational evidence support a benign effect (MetaRNN=0.26306117).
BP6
Variant 13-32319289-C-T is Benign according to our data. Variant chr13-32319289-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37803.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=6}. Variant chr13-32319289-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.280C>T | p.Pro94Ser | missense_variant | 3/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.280C>T | p.Pro94Ser | missense_variant | 3/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152174Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
7
AN:
152174
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251082Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135802
GnomAD3 exomes
AF:
AC:
12
AN:
251082
Hom.:
AF XY:
AC XY:
4
AN XY:
135802
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461562Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727096
GnomAD4 exome
AF:
AC:
56
AN:
1461562
Hom.:
Cov.:
32
AF XY:
AC XY:
25
AN XY:
727096
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000460 AC: 7AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74466
GnomAD4 genome
AF:
AC:
7
AN:
152292
Hom.:
Cov.:
33
AF XY:
AC XY:
7
AN XY:
74466
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
2
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Pro94Ser variant was identified by Caux-Moncoutier (2009) in a hereditary breast/ovarian cancer (HBOC) patient. The authors of this study used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. The variant was also identified in dbSNP (ID: rs80358531) “With non-pathogenic allele”, and three times in UMD as an unclassified variant. The p.Pro94 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Pro94Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 01, 2023 | In the published literature, the variant has been reported individuals with hereditary breast and ovarian cancer (PMID: 29928469 (2018) and 21120943 (2011)). Published studies indicate that this variant does not alter splicing (PMID: 32641407 (2020), 32123317 (2020)) and does not demonstrate allelic imbalance (PMID: 19471317 (2009)). The frequency of this variant in the general population, 0.00014 (5/34570 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21120943, 19471317, 25348012, 29659569, 29928469, 32641407, 32123317) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:3
| Benign, no assertion criteria provided | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Sep 01, 2023 | BS1(Supporting)+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) - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 22, 2012 | - - |
| Likely benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
not specified Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2023 | Variant summary: BRCA2 c.280C>T (p.Pro94Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.280C>T has been reported in the literature in individuals affected with breast or ovarian cancer and HBOC (example, Caux-Moncoutier_2009, Ortiz_2016, Maksimenko_2018, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed (BRCA1 c.5266dup, p.Gln1756fsX74 in UMD database), providing supporting evidence for a benign role. This variant had no effect in a study assessing allelic imbalance as an indirect measure of the impact of out-of-frame defects leading to reductions in the levels of mutant mRNA cleared through NMD (example, Caux-Moncoutier 2009). Consistent with this result, a second study has shown variant has no effect on splicing and classified the variant as benign (Thomassen_ 2022). This supports the notion that this variant has no effect on splicing. The following publications have been ascertained in the context of this evaluation (PMID: 19471317, 21120943, 29928469, 29659569, 35979650, 35264596). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 23, 2020 | DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.280C>T, in exon 3 that results in an amino acid change, p.Pro94Ser. This sequence change does not appear to have been previously described in patients with BRCA2-related disorders and has been described in the gnomAD database with a frequency of 0.014% in the Latino sub-population (dbSNP rs80358531). The p.Pro94Ser change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro94Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro94Ser change remains unknown at this time. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2019 | 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. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 28, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 17, 2017 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 12, 2023 | - - |
BRCA2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 11, 2024 | The BRCA2 c.280C>T variant is predicted to result in the amino acid substitution p.Pro94Ser. This variant was reported as uncertain significance in individuals with a personal or family history of hereditary breast and/or ovarian cancer (Table 1b, Caux-Moncoutier et al. 2009. PubMed ID: 19471317; Table S2B, Caux-Moncoutier et al. 2011. PubMed ID: 21120943; Patient 8 in Tables 2 and 3, Maksimenko et al. 2018. PubMed ID: 29928469). This variant was also documented in a prostate cancer cohort (Table S2, Paulo et al. 2018. PubMed ID: 29659569). Blood RNA analysis showed that this variant does not affect normal splicing (Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/37803). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Sep 11, 2024 | This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Vest4
MVP
MPC
0.071
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at