13-32357749-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):​c.7625C>T​(p.Thr2542Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2542T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 0.571
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 -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13077733).
BP6
Variant 13-32357749-C-T is Benign according to our data. Variant chr13-32357749-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96854.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.7625C>T p.Thr2542Met missense_variant 16/27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.7625C>T p.Thr2542Met missense_variant 16/275 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkuse as main transcriptc.7256C>T p.Thr2419Met missense_variant 16/271 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkuse as main transcriptn.7625C>T non_coding_transcript_exon_variant 15/262 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151930
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250756
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135616
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000754
AC:
11
AN:
1459242
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
726086
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00000901
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151930
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74204
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)May 01, 2012- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA2 p.Thr2542Met variant was identified in a Turkmen (Iranian) individual with esophageal squamous cell carcinoma (Akbari 2008), and was also identified in the COSMIC database. The p.Thr2542 residue is not conserved in mammals and the variant amino acid methionine (Met) is present in chimp, macaque, rat, dog, cat and opossum, increasing the likelihood that this variant does not have clinical significance. In addition, Akbari (2008) notes that structural crystallography in the region of the variant shows that the p.Thr2542 residue does not have a special role in the secondary structure of the BRCA2 protein. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 06, 2024Observed in patients with personal or family history of breast/ovarian cancer and in unaffected/cancer-free individuals (PMID: 16760289, 33471991, 32467295); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7853C>T; This variant is associated with the following publications: (PMID: 17724471, 22072316, 22425665, 16760289, 12228710, 33471991, 35464868, 29884841, 31853058, 32467295, 32947577) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 05, 2024The BRCA2 c.7625C>T (p.Thr2542Met) variant has been reported in the published literature in individuals with esophageal squamous cell carcinoma (PMID: 17724471 (2008)), breast cancer (PMID: 30982232 (2019)), and as c.7625T>C in a homozygous individual with Fanconi Anemia (PMID: 32947577 (2021)). This variant has also been seen in reportedly healthy individuals (PMID: 32467295 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). Prediction models suggest this variant has a neutral impact on function (PMIDs: 29884841 (2019), 31853058 (2020)). The frequency of this variant in the general population, 0.000004 (1/250756 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 10, 2022This missense variant replaces threonine with methionine at codon 2542 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast or ovarian cancer, and in an individual affected with esophageal cancer (PMID: 16760289, 1772447, 30982232). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 3/53461 unaffected controls, showing inconclusive association with disease (OR= 1.474 (95%CI 0.352 to 6.167)); p-value= 0.731; Leiden Open Variation Database DB-ID BRCA2_008612) (PMID: 33471991). This variant has been identified in 1/250756 chromosomes 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. -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 09, 2017This 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2023This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2542 of the BRCA2 protein (p.Thr2542Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer, esophageal squamous cell carcinoma, and/or Fanconi anemia (PMID: 17724471, 30982232, 32947577). ClinVar contains an entry for this variant (Variation ID: 96854). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. -
Likely benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateNov 16, 2021- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 27, 2023Variant summary: BRCA2 c.7625C>T (p.Thr2542Met) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250756 control chromosomes (gnomAD v2.1). c.7625C>T has been reported in the literature in heterozygous state in two individuals affected with breast- and/or ovarian cancer (Capalbo_2006, Wang_2019), and in a 73-year-old individual with esophageal carcinoma (Akbari_2008), however it was also reported in two healthy controls (Dong_2021 and in the FLOSSIES database). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, but was also found in 3/53461 controls (Dorling_2021, through LOVD). A recent study reported the variant in homozygous state in an infant affected with Fanconi Anemia, who was born from a consanguineous marriage, however no convincing evidence was provided that would confirm the pathogenic role of this variant, or would exclude the presence of other causative variants (Farah_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Medulloblastoma;C0040588:Tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 23, 2017- -
BRCA2-related cancer predisposition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 23, 2024- -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 10, 2024- -
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsSep 11, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
13
DANN
Benign
0.071
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.42
N
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.84
T
PrimateAI
Benign
0.22
T
PROVEAN
Benign
1.5
N;N
REVEL
Benign
0.18
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Vest4
0.32
MutPred
0.58
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP
0.76
MPC
0.020
ClinPred
0.016
T
GERP RS
1.3
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs80358989; hg19: chr13-32931886; COSMIC: COSV66461826; API