rs772662439
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000251.3(MSH2):c.2197G>A(p.Ala733Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A733D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2197G>A | p.Ala733Thr | missense_variant | 13/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2197G>A | p.Ala733Thr | missense_variant | 13/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251444Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135902
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461842Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727220
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74466
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 17, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2022 | 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 | Dec 13, 2022 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 12, 2022 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 13, 2019 | Variant summary: MSH2 c.2197G>A (p.Ala733Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251444 control chromosomes (gnomAD) among individuals of Eastern Asian and South Asian descent. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (4.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2197G>A has been reported in the literature in sequencing studies among individuals with carcinomas of ovarian/fallopian tube/peritoneal origin, medulloblastoma. breast cancer with family history, sporadic TNBC, and even one individual without a diagnosis of Lynch syndrome (Walsh_2011, Trubicka_2017, Kiyozumi_2019, Wang_2019, Yi_2019). These report(s), that are predominantly of Japanese/Chinese origin, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one of these reports the variant showed no-LOH, was MSI-Stable, had a normal IHC MSI panel, and was interpreted as benign (Walsh_2011). Co-occurrences with other pathogenic/likely pathogenic variant(s) have been reported in the literature (BRCA1 c.928C>T, p.Gln310*; MSH6 c.4055_4063dupAATTGCTGA, p.Lys1352_Leu1354dup), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance limited to two publications (Walsh_2011, Trubicka_2017). Based on the additional emerging evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 30, 2015 | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
MSH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2023 | The MSH2 c.2197G>A variant is predicted to result in the amino acid substitution p.Ala733Thr. This variant has been reported in one patient with pediatric medulloblastoma (Trubicka et al. 2017. PubMed ID: 28376765), three patients with breast and/or ovarian cancer (Table S2, Yi et al. 2019. PubMed ID: 30630526; Table S2, Wang et al. 2019. PubMed ID: 30982232), one patient with either primary ovarian, peritoneal, or fallopian tube carcinoma (Table S4, Walsh et al. 2011. PubMed ID: 22006311), and one patient with an unspecified cancer (Table S1, Kiyozumi et al. 2019. PubMed ID: 31386297). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47703697-G-A) and is interpreted as uncertain in ClinVar by the majority of laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/216350/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22006311, 28376765, 30630526, 30982232, 31386297, 32547938, 28706299, 18822302, 21120944, YangMengyuan2022, 33357406, 34755017, 33471991, 32980694) - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Ala733Thr variant was identified in 3 of 1886 proband chromosomes (frequency: 0.002) from individuals or families with medulloblastoma and hereditary breast and ovarian cancer (Walsh 2011, Trubicka 2017, Wang 2019). The variant was identified in dbSNP (rs772662439) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 3 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 12 of 251,444 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 6 of 18,394 chromosomes (freq: 0.0003), South Asian in 6 of 30,616 chromosomes (freq: 0.0002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European and Other populations. The p.Ala733 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at