13-32379412-G-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2
The NM_000059.4(BRCA2):c.8850G>T(p.Lys2950Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,613,836 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2950L?) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00075 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00082 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense
NM_000059.4 missense
Scores
7
9
Clinical Significance
Conservation
PhyloP100: 2.06
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-32379409-GA-GCT is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.023308098).
BP6
Variant 13-32379412-G-T is Benign according to our data. Variant chr13-32379412-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52692.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, not_provided=1, Benign=9, Uncertain_significance=2}. Variant chr13-32379412-G-T is described in Lovd as [Benign]. Variant chr13-32379412-G-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.8850G>T | p.Lys2950Asn | missense_variant | 22/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8850G>T | p.Lys2950Asn | missense_variant | 22/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.000756 AC: 115AN: 152202Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.000738 AC: 185AN: 250752Hom.: 0 AF XY: 0.000634 AC XY: 86AN XY: 135552
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GnomAD4 exome AF: 0.000820 AC: 1199AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.000816 AC XY: 593AN XY: 727044
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GnomAD4 genome 0.000755 AC: 115AN: 152320Hom.: 3 Cov.: 32 AF XY: 0.000725 AC XY: 54AN XY: 74496
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:28Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:9
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 09, 2019 | This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BP1,BP6. - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 25, 2011 | - - |
| Benign, criteria provided, single submitter | literature only | Counsyl | Jul 23, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Likely benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, no assertion criteria provided | clinical testing | Department of Medical and Surgical Sciences, University of Bologna | Sep 01, 2023 | BA1(Stand alone)+BS3(Strong)+BP4(Supporting)+BP5(Very Strong) 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) - |
not specified Uncertain:1Benign:7Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Lys2950Asn va riant in BRCA2 has been reported in at least 1 individual with BRCA2-associated cancer (Blay 2013). This variant has also been identified in 0.2% (21/11524) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs28897754). Computational prediction tools and conservation analysis suggest that the p.Lys2950Asn variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Lys2950Asn variant is uncertain, its f requency suggests that it is more likely to be benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 17, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2016 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 15, 2017 | - - |
| Benign, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Lys2950Asn variant was identified in 17 of 11804 proband chromosomes (frequency: 0.001) from individuals or families with Breast, Ovarian and Prostate Cancers, and was present in 2 of 1166 control chromosomes (frequency: 0.002) from healthy individuals (Diez_2003_12955716, Spurdle_2008_18375895, Akbari_2011_21965345, Beristain_2007_17262179, Borg_2010_20104584, Edwards_2003_12474142, Esteban-Cardenosa_2004_14684619, Gayther_2000_10969800, Miramar_2008_18176857, Romano_2007, Schoumacher_2001_11400546, Soegaard_2008_18559594, Soegaard_2008_18559594, Cavallone_2010_20694749). The variant was also identified in dbSNP (ID: rs28897754) “With Likely benign allele”, with a minor allele frequency of 0.0012(1000 Genomes Project) and with an average heterozygosity score with standard error of 0.002+/-0.035, increasing the likelihood that this is a benign variant. In NHLBI Exome Sequencing Project (Exome Variant Server) the variant was identified in 7 of 8600 European Americans and was not found in African Americans. In Exome Aggregation Consortium (ExAC) database the variant was identified in 21 of 11524 Latino alleles, 54 of 66378 European (Non Finnish) alleles, 5 of 6610 of Europeans (Finnish) alleles, increasing the likelihood this variant is a low frequency benign polymorphism in certain populations of origin. The variant was identified in the ClinVar database with conflicting classifications. It was classified as a benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), Ambry Genetics, Counsyl and Invitae; as likely benign by Emory Genetics, CHEO and GeneDX; as uncertain significance by BIC. The variant was identified in the BIC database (111X with unknown clinical importance), and in UMD (78X as a neutral variant). In UMD the variant was identified with co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.1483_1498del (p.Glu495IlefsX3), c.IVS5+2T>C, c.34C>T (p.Gln12X), c.3841C>T (p.Gln1281X), c.70T>C (p.Cys24Arg), c.IVS5+3A>G (c.212+3A>G); BRCA2: c.8904delC (p.Val2969CysfsX7), c.7007G>A (p.Arg2336His)), increasing the likelihood that the p.Lys2950Asn variant does not have clinical significance. The p.Lys2950 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the Asn (asparagine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Jan 06, 2016 | - - |
| 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2015 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 23, 2020 | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 19, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | BRCA2: BP4, BS2 - |
Hereditary breast ovarian cancer syndrome Benign:3
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 25, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2014 | - - |
Fanconi anemia complementation group D1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 17, 2023 | - - |
BRCA2-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 27, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of ubiquitination at K2950 (P = 0.0051);Loss of ubiquitination at K2950 (P = 0.0051);
MVP
MPC
0.17
ClinPred
T
GERP RS
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at