rs587781278

Positions:

• chr2-47480810-GAGAATCGCA-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BP6

The NM_000251.3(MSH2):​c.2576_2584del​(p.Glu859_Gln861del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G858G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MSH2 NM_000251.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:4
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3.
• BP6: Variant 2-47480810-GAGAATCGCA-G is Benign according to our data. Variant chr2-47480810-GAGAATCGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140785.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2576_2584del	p.Glu859_Gln861del	inframe_deletion	15/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2576_2584del	p.Glu859_Gln861del	inframe_deletion	15/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251448 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135896

Gnomad AFR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461832 Hom.: 0 AF XY: 0.0000908 AC XY: 66 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report - no effect on protein expression; ClinVar: 2 VUS -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2020	Variant summary: MSH2 c.2576_2584delAATCGCAAG (p.Glu859_Gln861del) results in an in-frame deletion that is predicted to remove three amino acids from helix-turn-helix domain in the encoded MSH2 protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2576_2584delAATCGCAAG has been reported in the literature in individuals affected with colon cancer and endometrial carcinoma (Plevova_2004, Casey_2005, Poynter_2008, Ring_2016). However, immunohistochemical analysis showed that there is no effect on expression of MLH1, MSH2 and MSH6 proteins (Plevova_2004, Casey_2005, Poynter_2008). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2019	- -

Lynch syndrome 1 Uncertain:4 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 20, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2023	This variant results in the in-frame deletion of three amino acids from the MSH2 protein, and has been reported in the published literature in individuals with endometrial cancer (PMID: 27443514 (2016)), and colorectal cancer in which the tumors were immunohistochemically positive for MSH2 expression (PMIDs: 18990764 (2008), 15713769 (2005), 15254659 (2004)). In a family study, this variant was characterized as being likely benign based on multifactorial analysis, and was identified in a cancer-free 72 year-old individual as well as in family members with colon polyps and pancreatic cancer (PMID: 30374176 (2019)). The frequency of this variant in the general population, 0.000039 (5/129166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	In-frame deletion of 3 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in individuals with endometrial or colorectal cancer (Plevova et al., 2004; Casey et al., 2005; Ring et al., 2016); Located in the critical helix-turn-helix domain (Lutzen et al., 2008; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 15713769, 18822302, 27720647, 27443514, 30374176, 18990764, 15254659, 24194902, 21120944) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MSH2: PM4, BP4 -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	This variant causes an in-frame deletion of three amino acids (Glu859-Gln861) in exon 15 of the MSH2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual each affected with endometrial and early onset colorectal cancer, in the latter case the tumor sample showed the presence of MSH2 by immunohistochemistry (PMID: 15713769, 18990764, 27443514). A multifactorial analysis based on family study data has reported this variant as likely benign due in part to cosegregation likelihood ratio of 0.2554 from one observed family (PMID: 30374176). This variant has been identified in 6/282854 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2022	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. -

Lynch syndrome Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

Apr 01, 2018

The MSH2 gene variant designated as NM_000251.2:c.2576_2584delAATCGCAAG (p.E859_Q861del) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.256:1 favoring a benign classification (Thompson et al., 2003, PMID:2900794). Data from a large reference laboratory cohort indicates that this variant was identified in many more individuals without MSH2 associated cancers than individuals affected with MSH2 associated cancers. In addition, the genomic position of this variant is not highly conserved, which also supports benign classification. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or cause an increased risk of Lynch syndrome associated cancers. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587781278; hg19: chr2-47707949;