rs11571833
Variant summary
Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BA1BP5_StrongBS3
This summary comes from the ClinGen Evidence Repository: The c.9976A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID:18451181, Internal lab contributor).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA026350/MONDO:0012933/097
Frequency
Consequence
NM_000059.4 stop_gained
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 -16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9976A>T | p.Lys3326* | stop_gained | Exon 27 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.9607A>T | p.Lys3203* | stop_gained | Exon 27 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*2034A>T | non_coding_transcript_exon_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*2034A>T | 3_prime_UTR_variant | Exon 26 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.00601 AC: 915AN: 152244Hom.: 3 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00660 AC: 1654AN: 250748 AF XY: 0.00683 show subpopulations
GnomAD4 exome AF: 0.00812 AC: 11863AN: 1461794Hom.: 69 Cov.: 31 AF XY: 0.00826 AC XY: 6006AN XY: 727208 show subpopulations
Age Distribution
GnomAD4 genome 0.00600 AC: 914AN: 152362Hom.: 3 Cov.: 32 AF XY: 0.00585 AC XY: 436AN XY: 74506 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:14Other:1
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The BRCA2 c.9976A>T variant is classified as Benign (BS2) -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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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. -
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not specified Benign:10Other:1
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not provided Benign:9
Variant summary: The BRCA2 c.9976A>T (p.Lys3326X) variant results in a termination codon at the penultimate exon, predicted to cause a truncation of the last 93 amino acids. This variant is not expected to affect any known domain (InterPro) and no truncations downstream of this position have been reported to be pathogenic in literature and databases. This variant was found in 2327/296226 control chromosomes (including 8 homozygotes) at a frequency of 0.0078555, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as benign (14)/likely benign (1). Available family, co-occurrence and functional data also show that it is not a disease causing variant. Despite these, this variant is found at considerably high frequency, especially in patients with breast and/or ovarian cancer, raising a possibilty that it may be a risk variant. Using weighted logistic regression, Meeks et al 2016 analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Other adjustments in the study were adjustment for attained age, consortium study site, and principal components of population structure. From the study, weighted ORs for invasive breast cancer and ovarian cancers were 1.28 (confidence interval 1.17-1.4; P-value=3.84x10e-3) and 1.26 (confidence interval 1.1-1.43; P-value=3.84x10e-3), respectively. The authors conclude that this study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Hence this variant is a risk allele which attributes a significant but a low risk in development of breast or ovarian cancer. In addition, other genetic/lifestyle/environmental factors may also be playing a part in elevation of risk. Taken together, this variant is classified as Benign for HBOC. -
BRCA2: BS2 -
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Hereditary breast ovarian cancer syndrome Uncertain:1Benign:4
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Hereditary cancer-predisposing syndrome Benign:3
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. -
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Breast and/or ovarian cancer Benign:2
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Malignant tumor of breast Benign:2
The BRCA2 p.Lys3326X variant was identified in 1577 of 158144 proband chromosomes (frequency: 0.010) from various ethnicities in multinational cohorts of individuals or families with breast and ovarian cancer and was present in 1414 of 167882 control chromosomes (frequency: 0.008) from healthy individuals (Hadjisavvas 2004 15172753, Wagner 1999 9971877, Borg 2010 20104584, Claes 2003 12759930, Meeks 2016 26586665). The variant was also identified in dbSNP (ID: rs11571833) as “With other allele”, ClinVar (Benign by ENIGMA, DVD CHOP, Michigan Medical Genetics, CSER_CC_NCGL University of Washington Medical Center, Colour Genomics, Prevention Genetics, Invitae, Counsyl, Ambry Genetics, Laboatroy Corporation of America Study Description, Children's Mercy Hospital, Fulgent, Cancer Genetic and Genomic Laboratory BC, EGL Genetic Diagnostics, Queen's University Department of Pathology, ARUP, Women's College Hospital, BIC, SCRP, and Biesecker Lab, as likely benign by Illumina, CHEO, and Pathway Genomics and as pathogenic by GeneReviews.), in ClinVitae (7x as Benign in 4 entries including 3 from ClinVar and 1 from EmyClass, as Conflicting interpretations of pathogenicity from Invitae and ClinVar, and as a polymorphism by kConFab), COSMIC (1x observed in alveolar rhabdomyosarcoma, as neutral), LOVD 3.0 (65x as does not affect function, affect unknown or unclassified), UMD-LSDB (114 entries, classified as neutral and reported as co-occuring with pathogenic BRCA2 and BRCA1 variants), BIC Database (301 entries, classification pending), and ARUP Laboratories (classified as not pathogenic or of no clinical significance). The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 111 individuals with breast, ovarian, pancreatic, or brain cancer. The variant was identified in control databases in 1782 of 276718 chromosomes (13 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 35 of 23984 chromosomes (freq: 0.001), Other in 48 of 6448 chromosomes (freq: 0.007), Latino in 95 of 34342 chromosomes (freq: 0.003), European Non-Finnish in 1089 of 126410 chromosomes (freq: 0.009), Ashkenazi Jewish in 41 of 10146 chromosomes (freq: 0.004), European Finnish in 266 of 25780 chromosomes (freq: 0.01), and South Asian in 208 of 30764 chromosomes (freq: 0.007) while the variant was not observed in the East Asian population. The c.9976A>T variant leads to a premature stop codon in the penultimate exon of BRCA2 and is predicted to cause a truncation of the last 93 amino acids. There is conflicting evidence in the literature regarding the significance of this variant. The variant was shown to have a 1.26 fold increase in breast cancer risk (in heterozygous form) or 5.78 increase risk (in homozygous form) (95% confidence interval p=1.2x10-5) and/or is in linkage disequilibrium with higher risk variants in a study looking at SNPs selected on the basis of genome wide association studies, genotyped in 45,290 cases and 41,880 controls from 41 studies (Michailidou 2013 23535729). A more recent study of the c.9976A>T variant identified 852/41081 carriers of the variant in women with breast cancer, and 322/14514 with ovarian cancer. They determined an odds ratio of adjusted for the probability of carrying a pathogenic BRCA1/2 variant of 1.28 for the breast cancer group, 1.52 for the triple negative breast cancer group and 1.46 for the serous ovarian cancer group (Meeks 2016 26586665). A posterior probability model integrating causality models based on prior probability derived from evolutionary conservation and likelihoods of causality, indicate that this variant is not pathogenic (Lindor_2012_21990134). However, in vitro splicing assays on 31 BRCA2 variants showed this variant to be pathogenic despite not being pathogenic ba -
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Fanconi anemia complementation group D1 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
BRCA2-related cancer predisposition Benign:1
The c.9976A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18451181, Internal lab contributor). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong). -
Familial cancer of breast Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at