rs267608058

chr2-47800129-ACAGT-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):c.2150_2153del(p.Val717AlafsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T716T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 3.10

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47800129-ACAGT-A is Pathogenic according to our data. Variant chr2-47800129-ACAGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 89256.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800129-ACAGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.2150_2153del	p.Val717AlafsTer18	frameshift_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.2150_2153del	p.Val717AlafsTer18	frameshift_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250930 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461862 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Val717AlafsX18 variant in MSH6 has been reported in 1 individual with endometrial cancer, 2 individuals with ovarian cancer, 3 individuals with colorectal cancer and 1 individual with Lynch syndrome (Walsh 2011, Baglietto 2010, Nilbert 2009, Pal 2012, Pagin 2013, Kolodner 1999, Hirasawa 2017). It has also been identified in 1/30612 of South Asian and in 1/34584 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89256). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 717 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Val717AlafsX18 variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2017	Variant summary: The MSH6 c.2150_2153delTCAG (p.Val717Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/121546 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, ExAC indicates that the location is a low-quality site, therefore, this observation needs to be cautiously considered. Multiple publications cite the variant in affected individuals including one family (Talseth-Palmer_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Reported in several individuals with colorectal, ovarian, and/or endometrial cancer, including multiple individuals with concordant tumor studies (Kolodner et al., 1999; Talseth-Palmer et al., 2010; Walsh et al., 2011; van Lier et al., 2012; Pagin et al., 2013); This variant is associated with the following publications: (PMID: 24763289, 22081473, 20487569, 23047549, 24728189, 18566915, 26845104, 22006311, 28724667, 28944238, 22658618, 29348823, 23652311, 30322717, 31054147, 32719484, 30787465, 33087929, 27535533, 35449176, 29922827, 28888541, 33511262, 33471991, 10537275) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2022	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/250930 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021)), ovarian cancer (PMID: 30322717 (2018), 29348823 (2017), 24728189 (2014)), and Lynch syndrome associated cancers (PMID: 31054147 (2019), 29345684 (2018), 28944238 (2017), 26845104 (2016)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2022	The MSH6 c.2150_2153delTCAG; p.Val717AlafsTer18 variant (rs267608058), also known as c.2147_2150delCAGT or 2149delTCAG, is reported in the literature in multiple individuals affected with Lynch syndrome and associated cancers (Baglietto 2010, DeRycke 2017, Hirasawa 2017, Kolodner 1999, Nilbert 2009, Pal 2012, Sun 2017, Talseth-Palmer 2010, Walsh 2011). This variant is also reported in ClinVar (Variation ID: 89256). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with various cancers and are considered pathogenic (Nilbert 2009, Pal 2012). Based on available information, this variant is considered to be pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201. PMID: 20028993 DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. PMID: 28944238 Hirasawa A et al. Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer. Oncotarget. 2017 Nov 28;8(68):112258-112267. PMID: 29348823 Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. PMID: 10537275 Nilbert M et al. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Fam Cancer. 2009;8(1):75-83. PMID: 18566915 Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. PMID: 23047549 Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. PMID: 28724667 Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5. PMID: 20487569 Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311 -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 04, 2021	This variant deletes 4 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in families affected with Lynch syndrome (PMID: 18566915, 20028993) and in individuals affected with ovarian cancer, endometrial cancer or colorectal cancer (PMID: 10537275, 22006311, 23047549). This variant has been identified in 2/250930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2021	The c.2150_2153delTCAG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 2150 to 2153, causing a translational frameshift with a predicted alternate stop codon (p.V717Afs*18). This mutation has been detected in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients, several with tumors demonstrating microsatellite instability and/or loss of MSH6 protein on immunohistochemistry (Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; van Lier MG et al. J Pathol, 2012 Apr;226:764-74; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Shirts BH et al. Genet Med, 2016 10;18:974-81; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Dow E et al. Intern Med J, 2018 Nov;48:1325-1330; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439), and was reported in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). In addition to the clinical data presented in the literature, This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 13, 2022	- -

Lynch syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 21, 2015	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Val717AlafsX18 deletion variant has been previously reported in the literature in 4 of 5340 proband chromosomes in individuals with either Lynch syndrome, colorectal cancer, endometriod or ovarian cancer, and it was absent from 378 control chromosomes (Kolodner 1999, Walsh 2011, Pal 2012, Nilbert 2008). The p.Val717AlafsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 717 and leads to a premature stop codon 18 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease for Lynch syndrome. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change creates a premature translational stop signal (p.Val717Alafs*18) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs587782275, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and associated cancers (PMID: 10537275, 18566915, 20028993, 22006311, 23047549, 23652311). ClinVar contains an entry for this variant (Variation ID: 89256). For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Sep 04, 2020

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs267608058; hg19: chr2-48027268;