rs267607911

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000251.3(MSH2):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 1,594,120 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 Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

MSH2
NM_000251.3 initiator_codon

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:15B:1

Conservation

PhyloP100: 7.84

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 42 pathogenic variants. Next in-frame start position is after 26 codons. Genomic position: 47403267. Lost 0.027 part of the original CDS.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000512

AC:

AN:

214858

AF XY:

0.0000428

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000860

AC:

124

AN:

1441876

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

715500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

41388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25670

East Asian (EAS)

AF:

0.00

AC:

AN:

38996

South Asian (SAS)

AF:

0.00

AC:

AN:

83220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.000110

AC:

121

AN:

1103722

Other (OTH)

AF:

0.0000503

AC:

AN:

59686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000838

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000499

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 27, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Initiator codon variant shown to produce multiple protein products including a full-length and a truncated transcript missing the first 25 amino acids through use of an in-frame alternate start codon (PMID: 21837758); Published functional studies are inconclusive: demonstrates impaired DNA binding and mismatch repair activity, but had no effect on MSH6 or MSH3 interaction, in one study and showed sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type in another study (PMID: 21837758, 33357406); Observed in individuals with MSH2-related cancers; however, tumor studies have shown microsatellite stability (MSS) or low levels of instability (MSI-L), and no loss of MSH2 protein expression (PMID: 10874307, 12624141, 16807412, 18033691, 23047549, 21837758, 25559809, 25479140, 29706558, 32809219, 34250417); This variant is associated with the following publications: (PMID: 12624141, 27476653, 10874307, 16807412, 18033691, 18781192, 23047549, 27064304, 24302565, 27153395, 28779004, 27449771, 28944238, 9718327, 25479140, 25559809, 29706558, 30728895, 26270727, 32338768, 29625052, 34541770, 33471991, 36451132, 34326862, 25639900, 33357406, 21837758, 32809219, 34250417, 36550560) -

Jan 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH2 c.1A>C variant disrupts the translation initiation codon of the MSH2 mRNA. However, an alternate initiation codon nearby may be utilized and experimental studies have shown cells carrying this variant produce both the full length protein and a truncated form of the MSH2 protein with the first 25 amino acids deleted. The shortened MSH2 protein has a small reduction in DNA mismatch repair (MMR) efficiency (PMID: 21837758 (2012)). In the published literature, this variant has been reported in individuals with gastric cancer (PMID: 29706558 (2018)), pancreatic cancer (PMID: 25479140 (2015)), squamous cell carcinoma (PMID: 26270727 (2015)), ovarian cancer (PMIDs: 23047549 (2012), 21837758 (2012)), and colorectal cancer (PMIDs: 34250417 (2021), 25559809 (2015), 18033691 (2008), 16807412 (2006), 10874307 (2000)). As evidence suggests, this variant may not cause classic Lynch syndrome as the affected colon cancer tumors are usually microsatellite instability-low (MSI-Low) with intact MSH2 expression (PMIDs: 28944238 (2017), 18033691 (2008)). This variant has also been shown to have neutral effect on MMR-associated cell survival in a massively parallel functional study (PMID: 33357406 (2021)). In addition, a different MSH2 start-loss variant (c.1A>G) has been reported in two siblings who carried a second MSH2 pathogenic variant. While both individuals had Lynch syndrome-associated cancers, neither developed constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 18781192 (2009)). The frequency of this variant in the general population, 0.00012 (13/110908 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. -

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1A>C (p.Met1?) variant in MSH2 has been reported in >10 individual with colorectal cancer (Otway 2000, Parc 2003, Barnetson 2006, Kets 2009, Cyr 2012, Rosenthal 2015, Chubb 2015) and has been identified in 0.01% (11/93132) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs267607911). This variant disrupts the translation initiation start codon (ATG) of MSH2 and has been shown to result in a truncated protein missing the first 25 residues (Cyr 2012). In vitro functional studies found that the truncated protein was capable of binding to MSH6 but only had slightly reduced activity compared to the wild type protein (Cyr 2012). The c.1A>C variant has been reported in trans with known pathogenic MSH2 variants in multiple individuals who did not have constitutional mismatch repair-deficiency, suggesting that the c.1A>C variant may not be disease causing (Kets 2009, Rosenthal 2015). Additionally, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000107358.2). In summary, the clinical significance of the c.1A>C variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, BP2. -

Hereditary cancer-predisposing syndrome

Uncertain:3

May 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the MSH2 gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Translation initiation may occur through use of CUG at the original start codon or may lead to a protein with a N-terminal truncation of 25 amino acids due to the presence of another downstream methionine at codon 26 (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). Studies of this truncated MSH2 (NΔ25) protein reflect an impaired ability to bind and cleave ATP, although it retains its ability to heterodimerize with MSH6 and MSH3 and it can still bind to mismatched DNA, albeit at a reduced rate (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). Transfection of a cDNA containing the c.1A>C alteration into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in mismatch repair activity (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts; however, tumors do not consistently demonstrate microsatellite instability and abnormal immunohistochemical staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep;63:749-59; Otway R et al. Hum. Mutat. 2000;16:61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Chubb D et al. J. Clin. Oncol., 2015 Feb;33:426-32; Grant RC et al. Gastroenterology, 2015 Mar;148:556-64; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). In another study, two siblings without constitutional mismatch repair deficiency (CMMRD) syndrome were reported to be compound heterozygous for an MSH2 start codon alteration and an MSH2 gross deletion and had an unusually severe Lynch tumor burden (Kets CM et al. Eur. J. Hum. Genet. 2009 Feb;17:159-64). This alteration has also been seen in a compound heterozygous state with an MSH2 truncation mutation in an individual who reportedly did not have features of CMMRD (Rosenthal ET et al. Clin. Genet. 2015 Dec;88:533-41). This amino acid position is highly conserved in available vertebrate species. Because of the conflicting evidence, the clinical significance of this variant remains unclear. -

May 22, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 08, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant alters the translation initiation codon methionine at codon 1 of the MSH2 protein. A functional study has shown that leucine encoded by c.1A>C variant could serve as a translation initiation site and results in the production of a full length protein that exhibits near normal activity (PMID: 21837758). In another functional study, the Met1Leu variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). It has also been shown that a downstream methionine at codon 26 may serve as an alternate translation initiation site at low levels and that recombinant MSH2 protein lacking the first 25 amino acids were largely functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). This variant has been observed in an individual affected with ovarian cancer with multiple Lynch syndrome-associated cancers in the family (PMID: 21837758), and an individual affected with early onset colorectal cancer (PMID: 28944238). A study of 14 carriers from eight families has suggested that the presence of this variant does not appear to be diagnostic of Lynch syndrome (PMID: 25639900). This variant has been observed in individuals affected with breast, prostate, pancreatic, and lung cancer (PMID: 25479140, 29625052, 32338768, 33471991), as well as in healthy unaffected individuals (PMID: 33471991). This variant has been identified in 13/246250 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. -

Lynch syndrome 1

Uncertain:2

Dec 16, 2015

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 17, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:2

Jun 21, 2019

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

Insufficient evidence -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant alters the translation initiation codon methionine at codon 1 of the MSH2 protein. A functional study has shown that leucine encoded by c.1A>C variant could serve as a translation initiation site and results in the production of a full length protein that exhibits near normal activity (PMID: 21837758). In another functional study, the Met1Leu variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). It has also been shown that a downstream methionine at codon 26 may serve as an alternate translation initiation site at low levels and that recombinant MSH2 protein lacking the first 25 amino acids were largely functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). This variant has been observed in an individual affected with ovarian cancer with multiple Lynch syndrome-associated cancers in the family (PMID: 21837758), and an individual affected with early onset colorectal cancer (PMID: 28944238). A study of 14 carriers from eight families has suggested that the presence of this variant does not appear to be diagnostic of Lynch syndrome (PMID: 25639900). This variant has been observed in individuals affected with breast, prostate, pancreatic, and lung cancer (PMID: 25479140, 29625052, 32338768, 33471991), as well as in healthy unaffected individuals (PMID: 33471991). This variant has been identified in 13/246250 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 specified

Uncertain:1

Apr 29, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH2 c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon, however experimental results demonstrate both downstream rescue by p.Met26 and incomplete loss of p.Met1 initiation (see below). Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 214858 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.1e-05 vs 0.00057), allowing no conclusion about variant significance. c.1A>C has been reported in the presumed heterozygous state in the literature in numerous individuals affected with clinical features of Hereditary Nonpolyposis Colorectal Cancer, for example HNPCC (Otway_2000), MSI-low sigmoid colon tumor who did not fulfill both the modified Amsterdam and Bethesda criteria (Barnetson_2006 and 2008), ovarian cancer who did not meet the Bethesda criteria for HNPCC (Cyr_2012), epithelial ovarian cancer (Pal_2012), serous and/or non-serous ovarian cancer (Kim_2020), colorectal cancer (Rosenthal_2015, DeRycke_2017), breast cancer (Desmond_2015), and diffuse gastric cancer (Fewings_2018). However, none of these cases had strong evidence for variant causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least 2 co-occurrences in trans with other pathogenic variant(s) have been reported in individuals with no evidence of autosomal recessive constitutional mismatch repair deficiency (CMMRD) (MSH2 exons 1-6del and MSH2 c.2038C>T, p.Arg680*; Rosenthal_2015). These reports provide some evidence for a possibly non-causative/benign role attributed to this variant, however a low penetrance phenotype cannot be ruled out. At least two publications report experimental evidence evaluating an impact on protein function in vitro. The most pronounced variant effect results in partially functional mismatch repair activity using a lentiviral expression system which found rescue of protein translation by the downstream p.Met26, however substantial translation initiation was also detected from the variant "CUG" at codon 1 (Cyr_2012). Another study reported a functionally moderate (per internal calculations ~40% of wild type MMR activity) outcome in a massively parallel assay system measuring sensitivity to 6-thioguanine(6-TG)(Jia_2021). Notably, p.Met1Lys/Thr/Ser/Arg/Ala/Ile all have <10% wild type MMR activity and p.Met1Val/Asp/Gln/Gly/His/Pro/Tyr have between 10-30% wild type MMR activity in this same system (Jia_2021). Further, there are several reports of p.Met1? (various c. changes) in HGMD associated with individuals affected with cancers. Together these data suggest that the clinical relevance of p.Met1? variants in MSH2 is uncertain. The following publications have been ascertained in the context of this evaluation (PMID: 9718327, 18033691, 16807412, 21837758, 10874307, 23047549, 25639900, 28944238, 26270727, 29706558, 33357406, 32809219, 34250417). ClinVar contains an entry for this variant (Variation ID: 90832). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

MSH2-related disorder

Uncertain:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH2 c.1A>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in individuals with ovarian (Pal et al. 2012. PubMed ID: 23047549), pancreatic (Table S1, Grant et al. 2015. PubMed ID: 25479140), prostate (Table S1, Nguyen-Dumont et al. 2020. PubMed ID: 32338768), colorectal (Barnetson et al. 2008. PubMed ID: 18033691; Table S1, DeRycke et al. 2017. PubMed ID: 28944238), and gastric cancers (Fewings et al. 2018. PubMed ID: 29706558). Disruptions of the MSH2 start codon in the NM_000251 transcript have been shown to result in a truncated MSH2 protein lacking the first 25 amino acids and biochemically confirmed to result in multiple protein products (in human cell lines) that may include the truncated and full-length forms of MSH2 and to reduce MMR efficiency slightly (Farrington et al. 1998. PubMed ID: 9718327; Cyr et al. 2012. PubMed ID: 21837758). However, the loss of MSH2 start codon has also been reported in at least three individuals without clinical features of constitutional mismatch repair deficiency syndrome, who had other pathogenic MSH2 variants in trans (Kets et al. 2009. PubMed ID: 18781192; Rosenthal et al. 2015. PubMed ID: 25639900). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90832/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is present in population databases (rs267607911, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with Lynch syndrome-associated cancers and also in unaffected individuals (PMID: 9718327, 10874307, 18033691, 18781192, 21837758, 23047549, 25639900, 27449771, 28944238). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90832). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is 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. -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH2 p.Met1? variant was identified in 5 of 8838 proband chromosomes (frequency: 0.001) from individuals or families with ovarian, colorectal, or pancreatic cancer and was not identified in 2844 control chromosomes from healthy individuals (Barnetson 2008, DeRycke 2017, Grant 2015, Otway 2000, Pal 2012). The variant was also identified in dbSNP (ID: rs267607911) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, Invitae, GeneDx, Ambry Genetics, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, UMD-LSDB (1x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors (2x uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or Zhejiang University databases. The variant was identified in control databases in 11 of 208952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant observed in European population in 11 of 93132 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1A>C p.Met1? variant occurs in the first base of the translation initiation site (the Methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. An in vivo MMR assay by Cyr (2012) suggests the variant may have a moderate impact on disease phenotype. This alteration leads to the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. Production of functional protein occurs through use of an alternative start codon at codon 26. In addition, the later study by Rosenthal (2015) published the case of two siblings with this variant in trans with a deletion of exons 1â€šÃ„Ã¬6 in MSH2, and no reported features of CMMR-D, and in trans with the pathogenic variant MSH2 c.2038C>T (p.Arg680*) in patient without reported features of CMMR-D. 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. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Uncertain:1

Feb 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inherited MMR deficiency (Lynch syndrome)

Benign:1

Sep 16, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS3_Strong,BS1_Strong,BP2_Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.45

T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.68

PhyloP100

7.8

PROVEAN

Benign

-1.4

N;.;N

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.52

P;.;P

Vest4

0.96

MutPred

1.0

Loss of methylation at K6 (P = 0.071);Loss of methylation at K6 (P = 0.071);Loss of methylation at K6 (P = 0.071);

MVP

0.98

ClinPred

0.99

GERP RS

5.4

PromoterAI

-0.74

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.97

gMVP

0.52

Mutation Taster

=3/197

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over