rs28897722
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4BP6_Very_Strong
The NM_000059.4(BRCA2):c.3682A>G(p.Asn1228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1228R?) has been classified as Pathogenic.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3682A>G | p.Asn1228Asp | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3682A>G | p.Asn1228Asp | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249496Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134860
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1459726Hom.: 0 Cov.: 35 AF XY: 0.0000468 AC XY: 34AN XY: 725924
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:8
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Asn1228Asp variant was identified in a minimum of 1 of 146 proband chromosomes (frequency: 0.007) from Italian individuals or families with breast/ovarian cancers (Giannini 2006). Computational methods assessing the pathogenicity of unclassified missense variants includes a posterior probability model/likelihood ratio model found the variant not to be deleterious (Lindor 2012, Easton 2007, Rajasekaran 2008). The variant was also identified in dbSBP (ID: rs28897722) “With other allele”, ClinVar (classified as benign, reviewed by an expert panel (last assessed 2015); submitters: benign by ENIGMA, Invitae, Ambry Genetics, SCRP (Sharing Clinical Reports Project, derived from Myriad reports); likely benign by GeneDx, Counsyl; uncertain significance by BIC and Div of Genomic Diagnostics, Children's Hospital of Philadelphia), Clinvitae (4x), LOVD 3.0 (4x), UMD-LSDB (7x with classification 1-Neutral), BIC Database (7x, unknown clinical importance, classification pending), and ARUP Laboratories (classified 1-not pathogenic or of no clinical significance). The variant was not identified in Genesight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 275416 chromosomes at a frequency of 0.00004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn1228 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; however, this information is not predictive enough to rule out pathogenicity. 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. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | 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 = 0.00000548 - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Oct 31, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2020 | Variant summary: BRCA2 c.3682A>G (p.Asn1228Asp) results in a conservative amino acid change located in the BRCA2 repeat of the encoded protein sequence. Three 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 249496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.3682A>G has been reported in the literature in cohorts of individuals with breast cancer (example, Capalbo_2006, DeBrakeleer_2015, Giannini_2006, Romano_2007, Seymour_2008, Maxwell_2016, Ikeda_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome for this variant (Lindor_2012). At-least two co-occurrences with another pathogenic variant have been reported in the BIC database (BRCA2 c.6468_6469delTC, p.Ser2156_Gln2157SerIlefs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function by a high throughput functional screen (Ikegami_2020). These results showed no damaging effect of this variant as measured by tolerance to treatment with PARP inhibitors. Eight clinical diagnostic laboratories and one expert panel (ENIGMA, classification as benign) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=4, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of conclusive evidence supporting an actionable outcome as outlined above and to reflect the majority consensus classification in the field, the variant was classified as benign. - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 24, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | BRCA2: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2020 | This variant is associated with the following publications: (PMID: 18724707, 27153395, 17924331, 24323938, 26010302, 16847550, 16760289, 21990134, 32444794) - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 10, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 14, 2021 | - - |
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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 20, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at