13-32336675-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000059.4(BRCA2):ā€‹c.2320A>Gā€‹(p.Thr774Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,754 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).

Frequency

Genomes: š‘“ 0.000053 ( 0 hom., cov: 32)
Exomes š‘“: 0.000042 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:14O:1

Conservation

PhyloP100: -0.352
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05243364).
BP6
Variant 13-32336675-A-G is Benign according to our data. Variant chr13-32336675-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37781.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=6, not_provided=1}. Variant chr13-32336675-A-G is described in Lovd as [Likely_benign]. Variant chr13-32336675-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.2320A>G p.Thr774Ala missense_variant 11/27 ENST00000380152.8 NP_000050.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.2320A>G p.Thr774Ala missense_variant 11/275 NM_000059.4 ENSP00000369497 A2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
250976
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.0000706
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000417
AC:
61
AN:
1461560
Hom.:
0
Cov.:
33
AF XY:
0.0000440
AC XY:
32
AN XY:
727084
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:
0.0000116
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000744
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:14Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:3
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)May 29, 2002- -
Benign, no assertion criteria providedclinical testingDepartment of Medical and Surgical Sciences, University of BolognaSep 01, 2023BS1(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) -
Uncertain significance, criteria provided, single submitterclinical testingCounsylFeb 12, 2016- -
Likely benign, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganApr 21, 2016- -
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Nov 19, 2009- -
Hereditary cancer-predisposing syndrome Benign:5
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 19, 2014This 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. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Aug 18, 2021- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 01, 2016- -
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsJul 12, 2017- -
Likely benign, criteria provided, single submittercurationUniversity of Washington Department of Laboratory Medicine, University of WashingtonMar 23, 2023Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not specified Benign:3Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 07, 2021Variant summary: BRCA2 c.2320A>G (p.Thr774Ala) results in a non-conservative amino acid change in 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-05 in 250976 control chromosomes, predominantly at a frequency of 7.1e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2320A>G has been reported in the literature in individuals affected with Breast or Prostate cancer and Ovarian Cancer as well as in a patient with macrocytic thrombocytopenia (example, Haiman_2013, Cunningham_2014, Kager_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in public databases such as UMD and BIC as well as our laboratory (UMD-BRCA2 c.5576_5579delTTAA, p.Ile1859fsX3; BRCA1 c.3700_3704delGTAAA, p.Val1234GlnfsX8; BRCA1 c.4065_4068delTCAA, p.Asn1355LysfsX10; BIC-BRCA1 c.3255_3256insGA, p.Arg1085_Leu1086?fs; Our laboratory-BRCA1 c.2722G>T, p.Glu908X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA2 p.Thr774Ala variant was not identified in the literature. The variant was identified in dbSNP (ID: rs55968715), the ClinVar database (classified as a benign variant by Ambry Genetics and by the Sharing Clinical Reports Project (derived from Myriad reports)), the BIC database (6X with unknown clinical importance), and UMD (3X as an unclassified variant). In UMD the variant was identified in one sample with a co-occurring pathogenic BRCA2 variant (c.5576_5579delTTAA (p.Ile1859LysfsX3)) and in another sample with a co-occurring pathogenic BRCA1 variant (c.4065_4068delTCAA (p.Asn1355LysfsX10), increasing the likelihood that the p.Thr774Ala variant does not have clinical significance. The variant was identified by the Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Thr774 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. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 02, 2018- -
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Uncertain significance, no assertion criteria providedclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Nov 09, 2021- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024BRCA2: BP4 -
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 06, 2019This variant is associated with the following publications: (PMID: 24817641, 24728327, 24504028, 25348012, 27633797, 23555315) -
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 09, 2023The BRCA2 c.2320A>G variant is predicted to result in the amino acid substitution p.Thr774Ala. This variant has been reported in an individual with congenital macrocytic thrombocytopenia that also harbored a variant in another gene (Kager et al. 2018. PubMed ID: 29797310, Supplemental data, Patient 13), an individual with ovarian cancer (Cunningham et al. 2014. PubMed ID: 24504028, Table S1), and multiple individuals in the Breast Information Core (BIC) database (Szabo et al. 2000. PubMed ID: 10923033, https://research.nhgri.nih.gov/projects/bic; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). It has also been reported in a cohort of healthy adults (Bodian et al. 2014. PubMed ID: 24728327, Table S1, referred to as rs55968715; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32910812-A-G) and has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37781). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
0.078
DANN
Benign
0.27
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.017
N
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.052
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-0.53
N;N
REVEL
Benign
0.16
Sift
Benign
0.13
T;T
Sift4G
Benign
0.45
T;T
Vest4
0.088
MVP
0.66
MPC
0.022
ClinPred
0.045
T
GERP RS
-7.5
gMVP
0.13

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: rs55968715; hg19: chr13-32910812; COSMIC: COSV99061626; COSMIC: COSV99061626; API