Submissions for variant NM_000179.3(MSH6):c.1705_1706del (p.Phe569fs)

dbSNP: rs587783056

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216742	SCV000274941	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-24	criteria provided, single submitter	clinical testing	The c.1705_1706delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides between positions 1705 and 1706, causing a translational frameshift with a predicted alternate stop codon (p.F569Hfs*7). This pathogenic mutation has been detected in an individual with colon cancer diagnosed at age 52 and a family history of endometrial cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). 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.
Invitae	RCV000542464	SCV000624682	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe569Hisfs*7) 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 (rs587783056, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 156507). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000216742	SCV000905451	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This variant deletes 2 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. To our knowledge, this variant has been reported in an individual referred for hereditary colorectal cancer screening (PMID: 28502729) and in an individual affected with colorectal cancer (PMID: 26023681). This variant has been identified in 1/31404 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	RCV000780461	SCV000917728	pathogenic	Lynch syndrome	2018-12-28	criteria provided, single submitter	clinical testing	Variant summary: The variant, MSH6 c.1705_1706delTT (p.Phe569HisfsX7) 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.1784delT (p.Leu595fsX15), c.2150_2153delTCAG (p.Val717fsX18)). The variant allele was found at a frequency of 3.2e-05 in 30970 control chromosomes. c.1705_1706delTT has been reported in the literature in an individual affected with colon cancer (Foley_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258039	SCV001434867	pathogenic	Lynch syndrome 5	2018-10-08	criteria provided, single submitter	clinical testing	The c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is predicted to introduce a premature translation termination codon and is extremely rare in general population. Therefore, the c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is classified as pathogenic.
Revvity Omics, Revvity	RCV003137645	SCV003822227	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing
GeneDx	RCV003137645	SCV003926442	pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing	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; Observed in individual(s) with a personal or family history consistent with pathogenic variants in this gene (Foley et al., 2015); Not observed at 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: 24362816, 31447099, 18269114, 34594420, 32686686, 32832836, 26023681)
Myriad Genetics, Inc.	RCV001258039	SCV004187407	pathogenic	Lynch syndrome 5	2023-08-15	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	RCV003462054	SCV004195825	pathogenic	Endometrial carcinoma	2023-03-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000780461	SCV004837740	pathogenic	Lynch syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The c.1705_1706del (p.Phe569Hisfs*7) variant in the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Phe569Hisfs*7), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 28514183, 23598716, 26023681, 31447099, 25479140, 30917047). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 156507). The variant is rare in the general population according to gnomAD (1/31404). Therefore, the c.1705_1706del (p.Phe569Hisfs*7) variant of MSH6 has been classified as pathogenic.
Pathway Genomics	RCV000144627	SCV000189954	pathogenic	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing