rs63750767

chr2-47806588-T-TTCAAAAGGGACATAGAAAA

Variant summary

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

The NM_000179.3(MSH6):c.3939_3957dup(p.Ala1320SerfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 1.23

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 2-47806588-T-TTCAAAAGGGACATAGAAAA is Pathogenic according to our data. Variant chr2-47806588-T-TTCAAAAGGGACATAGAAAA is described in ClinVar as [Pathogenic]. Clinvar id is 89486.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3939_3957dup	p.Ala1320SerfsTer5	frameshift_variant	9/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3939_3957dup	p.Ala1320SerfsTer5	frameshift_variant	9/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249986 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135216

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461432 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727018

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

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: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	The c.3939_3957dup (p.Ala1320Serfs*5) variant in the MSH6 gene is located on the exon 9 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Ala1320Serfs*5), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 27456091, 25980754, 26552419, 18809606, 19459153, 25186627). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 89486) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/249986). Therefore, the c.3939_3957dup (p.Ala1320Serfs*5) variant of MSH6 has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2019	Variant summary: MSH6 c.3939_3957dup19 (p.Ala1320SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249800 control chromosomes. c.3939_3957dup19 has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2003, Barnetson_2006, Chong_2009, Baglietto_2009, Kerr_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2017	The p.Ala1320fs variant in MSH6 has been reported in at least 10 individuals with MSH6-associated cancers, 1 individual with breast cancer, and 1 individual with prostate cancer (Barneston 2006, Chong 2009, Goodfellow 2003, Hampel 2008, Kerr 2016, Nowak 2017, Shirts 2016, Susswein 2015, Tung 2015, Yurgelun 2015). It also segregated with disease in one family (Buttin 2004). Tumors from many of these individuals demonstrated microsatellite instability and/or loss of MSH6 expression via IHC (Buttin 2004, Barneston 2006, Kerr 2016). This variant has also been reported in ClinVar (Variation ID 89486) and has been identified in 1/110290 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763673818). The p.Ala1320fs variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1320 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In addition, this variant was classified as pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108169.2). In summary, this variant is pathogenic. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1; PP4. -
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	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2023	PP4, PP5, PM2, PS4_moderate, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2020	The MSH6 c.3939_3957dup (p.Ala1320Serfs*5) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with a Lynch syndrome associated cancer including colorectal cancer (PMIDs: 18809606 (2008), 19459153 (2009), 25980754 (2015), 26552419 (2015), 26845104 (2016), 27456091 (2016), 28135145 (2017), 30729418 (2019), 31997046 (2020)), endometrial/ovarian cancer (PMIDs: 12732731 (2003), 26552419 (2015), 26681312 (2015), 32809219 (2020)), breast cancer (PMID: 25186627 (2015)), and prostate cancer (PMIDs: 27456091 (2016), 30337059 (2019)). The frequency of this variant in the general population, 0.000004 (1/249986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	The MSH6 c.3939_3957dup; p.Ala1320SerfsTer5 variant (rs63750767), has been described in the literature in multiple individuals with Lynch syndrome (Carter 2018, Chong 2009, Goodfellow 2003, Kerr 2016). This variant is also reported in ClinVar (Variation ID: 89486). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant creates a frameshift by duplicating 19 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Chong G et al. High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families. Hum Mutat. 2009; 30(8):E797-812. Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003; 100(10):5908-13. Kerr L et al. A cohort analysis of men with a family history of BRCA1/2 and Lynch mutations for prostate cancer. BMC Cancer. 2016 Jul 25;16:529. PMID: 27456091. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2022	Frameshift variant predicted to result in protein truncation 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; This variant is associated with the following publications: (PMID: 18809606, 12732731, 25980754, 15952900, 19459153, 16807412, 26681312, 27456091, 27863258, 24100870, 21155762, 17531815, 28135145, 26845104, 26552419, 25186627, 16464007, 20028993, 30322717, 32719484, 34086170, 27535533) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This variant inserts 19 nucleotides in exon 9 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 individuals affected with Lynch syndrome (PMID: 16807412, 19459153, 27456091), colorectal cancer (PMID: 18809606, 26845104) and endometrial and/or ovarian cancer (PMID: 26552419, 26681312). This variant has been identified in 1/249986 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	Sep 10, 2018	The c.3939_3957dup19 pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of 19 nucleotides at positions 3939 to 3957 causing a translational frameshift with a predicted alternate stop codon (p.A1320Sfs*5). This mutation was detected in a French-Canadian family meeting Amsterdam II criteria for Lynch syndrome. The proband had MSH6-deficient endometrial cancer diagnosed at age 50 and a strong family history of colon, kidney, uterine, and cervical cancers (Chong G et al. Hum. Mutat. 2009 Aug;30:E797-812). It has also been identified in a patient who was diagnosed with endometrial cancer at age 47 (Goodfellow PJ et al. Proc. Natl. Acad. Sci. USA. 2003 May;100:5908-13), a male diagnosed with an MSI-H cecal tumor at age 54 (Hampel H et al. J. Clin. Oncol. 2008 Dec;26(35):5783-5788), and in a proband with prostate cancer whose tumor showed loss of MSH6 on IHC (Kerr L et al. BMC Cancer. 2016 Jul;16:529). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 28, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Ala1320SerfsX5 variant was identified in 5 of 1892 proband chromosomes (frequency: 0.003) from American, French Canadian and Scottish individuals or families with endometrial or colon cancer (Goodfellow 2015, Goodfellow 2003, Barnetson 2006, Chong 2009). The variant was also identified in a patient with endometrial/ovarian cancer through NGS cancer panel testing of over 10,000 consecutive cases referred for cancer testing (Susswein 2015). Buttin et al. (2004) investigated the expressivity and penetrance of pathogenic MSH6 variants (this duplication variant included) seen in endometrial cancer probands and found there is an increased cancer risk with these mutations (tumour spectrum not defined), the penetrance could be as high as 58%, and, cancer is later age onset compared to MSH2/MLH1 mutations. The variant was also identified in dbSNP (ID: rs763673818), Clinvitae database (classification pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), and the ClinVar database (classification pathogenic, reviewed by an expert panel, submitters: InSIGHT, Ambry Genetics, GeneDx, Mayo Clinic). The c.3939_3957dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1320 and leads to a premature stop codon 5 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 in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Apr 15, 2022

PVS1, PS3_Moderate, PM2; no PS4 due to this case being apparently homozygous for recessive disorder -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Ala1320Serfs*5) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs763673818, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, endometrial and ovarian cancer, and/or Lynch syndrome (PMID: 18809606, 19459153, 25186627, 25980754, 26552419, 26681312, 26845104, 27456091). ClinVar contains an entry for this variant (Variation ID: 89486). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6) have been determined to be pathogenic (PMID: 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

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: rs63750767; hg19: chr2-48033727;