Submissions for variant NM_000535.7(PMS2):c.949C>T (p.Gln317Ter)

dbSNP: rs143277125

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076902	SCV000108399	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000570620	SCV000670801	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-20	criteria provided, single submitter	clinical testing	The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been previously reported in an individual with colorectal carcinoma diagnosed at age 39 years whose tumor showed loss of PMS2 on immunohistochemical staining (Senter L et al. Gastroenterology. 2008 Aug;135:419-28). It has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency (CMMRD), whose clinical features included a diagnosis of medulloblastoma at age 8 years, ampullary adenocarcinoma at 16 years, and multiple café au lait macules (Senter L et al. 2008). 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	RCV000686600	SCV000814125	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-08	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 18602922, 19283792). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln317*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). ClinVar contains an entry for this variant (Variation ID: 91383). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001536747	SCV001753553	pathogenic	not provided	2021-04-27	criteria provided, single submitter	clinical testing	Nonsense 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 patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Senter 2008); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 18709565, 22577899, 20531397, 21376568, 19283792, 18602922, 25525159)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325181	SCV004031208	pathogenic	Lynch syndrome 4	2023-06-26	criteria provided, single submitter	clinical testing	The PMS2 c.949C>T (p.Gln317Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant has been reported as heterozygous in an individual with colon cancer (PMID: 18602922). It has also been observed as homozygous in an individual with constitutional mismatch repair deficiency who presented with medulloblastoma at 8 years of age, adenocarcinoma at 16 years of age, and multiple café-au-lait macules; the adenocarcinoma tumor showed loss of PMS2 on immunohistochemical staining (PMID: 18602922, 19283792). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Myriad Genetics, Inc.	RCV003325181	SCV004187687	pathogenic	Lynch syndrome 4	2023-09-19	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.
Baylor Genetics	RCV003325181	SCV004207862	pathogenic	Lynch syndrome 4	2023-03-27	criteria provided, single submitter	clinical testing