chr2-47466813-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1661+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000251.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250972Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459884Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726360
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12362047, 33259954, 27601186]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 32849802, 12362047]. -
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not provided Pathogenic:2
MSH2: PVS1, PM2, PS4:Moderate -
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12362047, 25081409, 27601186, 33259954, 32849802, 36425062, 16451135, 11879922) -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change falls in intron 10 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs267607972, gnomAD 0.0009%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 12362047, 25081409; Invitae). ClinVar contains an entry for this variant (Variation ID: 90721). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 12362047, 32849802; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1661+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 10 in the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in a Polish Lynch syndrome family and was shown to cause skipping of exon 10 leading to the creation of a new stop codon (Kurzawski G et al. J. Med. Genet., 2002 Oct;39:E65). This alteration has also been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835) and in an individual with endometrial cancer whose tumor showed microsatellite instability and loss of MSH2 protein staining via immunohistochemisty (Ferguson SE et al. Cancer, 2014 Dec;120:3932-9). In addition, this allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Endometrial carcinoma Pathogenic:1
The MSH2 c.1661+5G>C variant was identified in 3 out of 832 proband chromosomes (frequency 0.004) in Polish individuals having met Amsterdam II criteria or suspected of having Lynch Syndrome; and Canadian individuals with endometrial cancer (Kurzawski 2002, Kurzawski 2006, Ferguson 2014). The variant was also identified in dbSNP (ID: rs267607972) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), InSiGHT Colon Cancer Gene Variant Database (LOVD) (4X, as unknown pathogenicity), the ClinVar database (classification uncertain significance, reviewed by an expert panel), 1000 Genomes Project in 1 of 125000 chromosomes (frequency: 0.000008), and the Exome Aggregation Consortium database (March 14, 2016) in 1 of 121162 chromosomes (freq. 000008) in a population of European (Non-Finnish) individuals in 1 of 66680 chromosomes (freq. 0.000015), and none from South Asian, Latino, African, East Asian, European (Finnish) or Other populations. The c.1661+5G>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. The nature of the previously unreported c.1661+5G>C variant was confirmed at the RNA level (from fresh lymphocytes) with the identification of an aberrant transcript which caused skipping of exon 10 and creation of a downstream stop codon (p.Gly504_Ser554>AlafsX3, Kurzawski 2002, Kurzawski 2006). The variant was also identified by our laboratory in 2 individuals with endometrial cancer (one with reported tumour IHC deficiency) and was not identified by familial variant testing for eight reportedly unaffected individuals from 3 separate families. In summary, based on the above information, this variant is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at