chr13-32344651-A-T
Variant summary
Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2
The NM_000059.4(BRCA2):c.6935A>T(p.Asp2312Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000141 in 1,558,374 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2312E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Benign. The variant received -11 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | MANE Select | c.6935A>T | p.Asp2312Val | missense splice_region | Exon 12 of 27 | NP_000050.3 | ||
| BRCA2 | NM_001432077.1 | c.6935A>T | p.Asp2312Val | missense splice_region | Exon 12 of 27 | NP_001419006.1 | |||
| BRCA2 | NM_001406720.1 | c.6935A>T | p.Asp2312Val | missense splice_region | Exon 12 of 27 | NP_001393649.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | TSL:5 MANE Select | c.6935A>T | p.Asp2312Val | missense splice_region | Exon 12 of 27 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000544455.6 | TSL:1 | c.6935A>T | p.Asp2312Val | missense splice_region | Exon 12 of 27 | ENSP00000439902.1 | ||
| BRCA2 | ENST00000530893.7 | TSL:1 | c.6566A>T | p.Asp2189Val | missense splice_region | Exon 12 of 27 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152100Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000244 AC: 61AN: 249766 AF XY: 0.000369 show subpopulations
GnomAD4 exome AF: 0.000149 AC: 209AN: 1406156Hom.: 4 Cov.: 27 AF XY: 0.000202 AC XY: 142AN XY: 702668 show subpopulations
Age Distribution
GnomAD4 genome 0.0000723 AC: 11AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74418 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:5
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000027
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Hereditary cancer-predisposing syndrome Benign:5
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.
BA1, BS3, PP3 c.6935A>T, located in exon 12 of the BRCA2 gene, is predicted to result in the in the substitution of aspartic acid by valine at codon 2312, p.(Asp2312Val). This position is outside a (potentially) clinically important functional but the SpliceAI algorithm predicts a slight effect on the splicing donor site of intron 12 (deltascore=0.22; ALT score=0.73) and activates a cryptic splice donor site: one nucleotide upstream (deltascore=0.14, ALT score=0.14)(PP3). This missense variant shown to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by two calibrated studies incorporating mRNA splicing effect to affect function similar to benign control variants (PMID:29988080, 33293522) (BS3) The variant allele was found in 58/30450 alleles, with a filter allele frequency of 0.14% at 99% confidence in the gnomAD v2.1.1 database (South Asian exome non-cancer data set)(BA1). This variant has been reported in ClinVar (1x uncertain significance, 10x likely benign, 9x benign) and LOVD (5x uncertain significance, 6x benign, 3x not classified) databases and in BRCA Exchange database as benign (“IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000027”). Based on currently available information, the variant c.6935A>T is classified as a benign variant according to ClinGen- BRCA1 and BRCA2 Guidelines version 1.0.0.
not provided Benign:4
The BRCA2 p.Asp2312Val variant was identified in 3 of 4718 proband chromosomes (frequency: 0.0006) from Brazilian, German and Other individuals or families at high risk of breast and ovarian cancers, and was present in 1 of 230 control chromosomes (frequency: 0.004) from healthy elderly Croatian women (Fernandes 2016, Trujillano_2015, Brandao 2011). The variant was identified by Brandao (2011) in an individual from a high-risk breast and/or ovarian cancer family and RT-PCR transcript analysis of lymphocytes from this individual showed an increase in exon12 skipping as compared to normal controls; however, the BRCA2 exon 12 deletion isoform is naturally occurring and the c.6935T allele expressed full-length transcript at similar expression levels compared with the wild-type (WT) allele and control alleles suggesting the variant is likely to be neutral. Li (2009) studied a different variant in this region which was also shown to increase exon 12 skipping, and functional results from this study did not detect any difference between this variant and wild type, suggesting that exon 12 is functionally redundant and missense changes in this region are likely to be neutral. In addition, Li (2009) notes that the peptide encoded by exon 12 does not contain any known important functional motifs; however, this region may have a role in processes that were not assessed. An in silico likelihood-ratio study by Easton (2007) suggests that this variant is neutral. In addition, a splice study using 6 in silico models, with predictions compared to transcript analysis showed the variant does not effect change on splicing (Houdayer 2012). The variant was also identified in dbSNP (ID: rs80358916), ClinVar (with conflicting interpretations of pathogenicity; classified as benign by Ambry Genetics, Counsyl, Invitae; likely benign by Prevention Genetics, Div of Genomic Diagnostics - Children's Hospital of Philadelphia, Illumina Clinical Services, GeneDx; and uncertain significance by BIC), Clinvitae (5X), LOVD 3.0 (4x), UMD-LSDB (10X, 1-neutral), and the BIC Database (5x, clinical importance unknown, classification pending). The variant was not identified in the COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was also identified in control databases in 64 (1 homozygous) of 276074 chromosomes at a frequency of 0.0002 in the following populations: other in 1 of 6424 chromosomes (freq. 0.00016), European in 2 of 126058 chromosomes (freq. 0.000016), Ashkenazi Jewish in 1 of 10110 chromosomes (freq. 0.0001), South Asian in 60 of 30712 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The variant was also identified by our laboratory in 3 individuals with breast and ovarian cancer. The p.Asp2312 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp2312Val variant occurs in the 3rd last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign
Variant summary: The BRCA2 c.6935A>T (p.Asp2312Val) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict damaging outcome for this variant. This variant is only three nucleotides away from the nearest exon-intron boundary and is thus predicted to affect normal splicing. 3/5 splice prediction tools predict a significant impact on normal splicing. But in vitro studies show that this variant does not significantly affect normal splicing (Houdayer_2011, Brandao_2011). This variant was found in 32/113924 control chromosomes (including one homozygote), predominantly observed in the South Asian, subpopulation at a frequency of 0.0016915 (27/15962). This frequency is about 2 times higher than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian. This variant has been reported in several instances in HBOC patients and/or individuals undergoing BRCA1/2 testing including co-occurrence with another deleterious variant (p.Lys1026Ter) in the same gene, strongly supporting for the benign outcome. Multifactorial probability-based models are also consistent with the benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant is currently classified as Likely Benign.
BRCA2: BP1, BP2, BS3:Supporting, BS1
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Hereditary breast ovarian cancer syndrome Benign:2
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;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 Benign:1
BRCA2-related cancer predisposition Benign:1
Fanconi anemia complementation group D1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Inherited ovarian cancer (without breast cancer) Benign:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at