Submissions for variant NM_000179.3(MSH6):c.2105C>G (p.Ser702Ter)

dbSNP: rs63751419

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074717	SCV000107924	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000629877	SCV000750833	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89253). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 14974087). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser702*) 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).
Ambry Genetics	RCV001014449	SCV001175157	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-26	criteria provided, single submitter	clinical testing	The p.S702* pathogenic mutation (also known as c.2105C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2105. This changes the amino acid from a serine to a stop codon within coding exon 4. While this exact mutation has not been reported in the literature, a close match (c.2105C>A) giving rise to the same premature stop codon at amino acid position 702 has been reported in an individual diagnosed with colon, uterine, and ovarian cancer, with concordant tumor data showing loss of MSH6 via immunohistochemistry (Plaschke J et al. Hum. Mutat. 2004 Mar;23(3):285). 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.
Fulgent Genetics, Fulgent Genetics	RCV002490669	SCV002800119	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-04-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450941	SCV004187267	pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.