rs780178752
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000251.3(MSH2):c.159C>T(p.Ala53=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A53A) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.159C>T | p.Ala53= | synonymous_variant | 1/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.159C>T | p.Ala53= | synonymous_variant | 1/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000430 AC: 1AN: 232784Hom.: 0 AF XY: 0.00000785 AC XY: 1AN XY: 127354
GnomAD4 exome AF: 0.00000618 AC: 9AN: 1455742Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5AN XY: 723696
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74386
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 21, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2014 | This alteration is classified as likely 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. - |
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 05, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 20, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Endometrial carcinoma Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Ala53= variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database,. The variant was identified in dbSNP (ID: rs780178752) “With Likely benign allele”, ClinVar (classified likely benign Ambry Genetics, Invitae, GeneDx, and Color Genomics Inc.), Clinvitae (3x), and in control databases in 1 of 228468 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 102020 chromosomes (freq: 0.00001), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was also identified by our laboratory in 1 individual with endometrial and breast cancer, co-occurring with a pathogenic MSH6 variant (c.3938_3941dup, p.Gln1314HisfsX6), increasing the likelihood the variant does not have clinical significance. The p.Ala53= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at