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):āc.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
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2320A>G | p.Thr774Ala | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250976Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135682
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461560Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727084
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74352
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:3
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 12, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 19, 2009 | - - |
Hereditary cancer-predisposing syndrome Benign:5
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2014 | This 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 submitter | curation | Sema4, Sema4 | Aug 18, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 01, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jul 12, 2017 | - - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense 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 provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2021 | Variant 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 provided | clinical testing | Department 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 submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 02, 2018 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Nov 09, 2021 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | BRCA2: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2019 | This variant is associated with the following publications: (PMID: 24817641, 24728327, 24504028, 25348012, 27633797, 23555315) - |
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2023 | The 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at