Submissions for variant NM_000179.3(MSH6):c.3660_3663dup (p.Phe1222fs)

gnomAD frequency: 0.00001  dbSNP: rs752404604

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492020	SCV000580324	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The c.3660_3663dupAACA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of AACA at nucleotide position 3660, causing a translational frameshift with a predicted alternate stop codon (p.F1222Nfs*3). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588486	SCV000695882	likely pathogenic	Lynch syndrome	2019-05-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3660_3663dupAACA (p.Phe1222AsnfsX3) 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 (eg. c.3699_3702delAGAA (p.Lys1233fsX6), c.3799_3800delAT (p.Met1267fsX7)). The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3660_3663dupAACA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One other submitter have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000799829	SCV000939511	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-11-09	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428406). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Phe1222Asnfs*3) 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). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003449327	SCV004185629	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000588486	SCV004848536	likely pathogenic	Lynch syndrome	2023-02-06	criteria provided, single submitter	clinical testing	The p.Phe1222AsnfsX3 variant in MSH6 has not been previously reported in individuals with MSH6-associated cancers but has been reported by other clinical laboratories in ClinVar (Variation ID 428406). It has also been identified in 0.002% (1/41412) of African/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org, gnomAD v3.1.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1222 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.