Variant rs759912716 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000251.3(MSH2):c.2595_2597del(p.Ile865del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000041 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I865I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MSH2
NM_000251.3 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2595_2597del	p.Ile865del	inframe_deletion	15/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2595_2597del	p.Ile865del	inframe_deletion	15/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251438

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461836

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2024	The c.2595_2597delCAT variant (also known as p.I865del) is located in coding exon 15 of the MSH2 gene. This variant results from an in-frame CAT deletion at nucleotide positions 2595 to 2597. This results in the in-frame deletion of an isoleucine at codon 865. This alteration has been reported in a Taiwanese family meeting Amsterdam II criteria; however, the family was also noted to carry the c.1846_1848delAAG pathogenic alteration in the MLH1 gene (Kamiza AB et al. PLoS ONE, 2015 Jun;10:e0130018). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2023	This variant causes an in-frame deletion of one amino acid of the MSH2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 26053027). However, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype. This variant has also been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

MSH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

The MSH2 c.2595_2597delCAT variant is predicted to result in an in-frame deletion (p.Ile865del). This variant was previously reported in an individual in a large cohort of patients with suspected Lynch syndrome (Bunya Kamiza et al. 2015. PubMed ID: 26053027). This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47707968-TATC-T). In the ClinVar database, this variant has been listed as 'uncertain' by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/421318/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 04, 2023

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 08, 2023

This variant causes an in-frame deletion of one amino acid of the MSH2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 26053027). However, this individual also carries a pathogenic variant in the MLH1 gene, suggesting c.2595_2597del in MSH2 may not be disease-causing. This variant has also been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2016

This in-frame deletion of 3 nucleotides in MSH2 is denoted c.2595_2597delCAT at the cDNA level and p.Ile865del (I865del) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATAT[CAT]GGAA. This deletion of a single Isoleucine residue occurs at a position that is not conserved and is located in the helix-turn-helix domain (Lutzen 2008). This variant was observed in at least one family who meets Amsterdam II criteria for Lynch syndrome; however, this family was also found to carry a pathogenic variant in MLH1 (Kamiza 2015). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear. We consider MSH2 Ile865del to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This variant, c.2595_2597del, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Ile865del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759912716, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421318). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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