Submissions for variant NM_000179.3(MSH6):c.3573dup (p.Val1192fs)

dbSNP: rs1057517764

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413655	SCV000490623	pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.3573dupT at the cDNA level and p.Val1192CysfsX2 (V1192CfsX2) at the protein level. The normal sequence, with the base that is duplicated in braces, is ATTTTT[T]GTTG. The duplication causes a frameshift, which changes a Valine to a Cysteine at codon 1192 and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3573dupT has been observed in one individual with endometrial cancer demonstrating absence of MSH6 protein on immunohistochemistry whose family met revised Bethesda Criteria guidelines, as well as in one individual from a multiple colorectal cancer or Lynch syndrome family (Baglietto 2010, Buchanan 2014). We consider this variant to be pathogenic.
Invitae	RCV000684804	SCV000551108	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 372414). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Val1192Cysfs*2) 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 (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with endometrial cancer and Lynch syndrome (PMID: 24323032, 27064304).
Ambry Genetics	RCV000490868	SCV000580187	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	clinical testing	The c.3573dupT pathogenic mutation, located in coding exon 7 of the MSH6 gene, results from a duplication of T at nucleotide position 3573, causing a translational frameshift with a predicted alternate stop codon (p.V1192Cfs*2). This mutation has been reported in multiple families with Lynch syndrome (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; Kwong A et al. J Mol Diagn, 2020 04;22:544-554; Brand RE et al. Fam Cancer, 2020 04;19:169-175), including a patient with MSH6-deficient endometrial cancer (Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32(2):90-100) and a colorectal cancer patient with concordant IHC results (Latham A et al. J Clin Oncol, 2019 02;37:286-295). This mutation is also designated as c.3572-3573insT in published literature. 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.
Color Diagnostics, LLC DBA Color Health	RCV000490868	SCV000685416	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 7 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 identified in 1/245904 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192428	SCV001360541	pathogenic	Hereditary nonpolyposis colon cancer	2019-05-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3573dupT (p.Val1192CysfsX2) 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 (e.g. c.3609_3612delTGCA (p.His1203fsX12), c.3699_3702delAGAA (p.Lys1233fsX6), and c.3799_3800delAT (p.Met1267fsX7)). The variant was absent in 250974 control chromosomes (gnomAD). The variant, c.3573dupT, has been reported in the literature in at least one individual affected with endometrial cancer, with the absence of MSH6 protein expression in the tumor tissue (Baglietto 2010, Buchanan_2014, Sjursen_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002466494	SCV002761464	pathogenic	Lynch syndrome 5	2021-06-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002466494	SCV004185644	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003470358	SCV004197616	pathogenic	Endometrial carcinoma	2023-10-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995915	SCV004835095	pathogenic	Lynch syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The c.3573dup (p.Val1192Cysfs*2) variant in the MSH6 gene is located on the exon 7 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val1192Cysfs*2), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals affected with Lynch syndrome-associated cancers (PMID: 32068069, 29368341, 27064304, 30376427, 24323032, 32459922). Loss-of-function variants located downstream to this position have been reported in individuals with Lynch syndrome (PMID: 20028993). The variant is reported in ClinVar as pathogenic (ID: 372414). This variant is absent in the general population database (gnomAD). Therefore, the c.3573dup (p.Val1192Cysfs*2) variant of MSH6 has been classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000460316	SCV000592650	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.3573dup OR p.Val1192Cys_fsX2 variant has been reported in 1 proband with a Lynch syncrome related cancer (Baglietto_2009_20028993). The p.Val1192Cys_fsX2 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1192 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the MSH6 gene. In summary, based upon the above information, this variant meets are criteria for pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413655	SCV000691941	pathogenic	not provided		no assertion criteria provided	clinical testing