Submissions for variant NM_000535.7(PMS2):c.809C>G (p.Ser270Ter)

gnomAD frequency: 0.00001  dbSNP: rs786201047

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162437	SCV000212785	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	The p.S270* pathogenic mutation (also known as c.809C>G), located in coding exon 8 of the PMS2 gene, results from a C to G substitution at nucleotide position 809. This changes the amino acid from a serine to a stop codon within coding exon 8. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000162437	SCV000691119	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 28514183), and an individual affected with colorectal cancer (PMID: 25856668). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629674	SCV000750630	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser270*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Lynch syndrome (PMID: 25856668, 28514183). ClinVar contains an entry for this variant (Variation ID: 183732). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657645	SCV000779391	pathogenic	not provided	2023-05-15	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; 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; Observed in individuals with a personal and/or family history consistent with pathogenic variants in this gene, as well as an unaffected individual with a family history of breast cancer (Goodenberger et al., 2016; Espenschied et al., 2017; Roberts et al., 2018; Ten Broeke et al., 2018); This variant is associated with the following publications: (PMID: 25856668, 29345684, 32090079, 30787465, 30161022, 28904067, 28514183)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657645	SCV000888417	pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing	The PMS2 c.809C>G (p.Ser270*) variant causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in an individual affected with colorectal cancer (PMID: 25856668 (2015)). The frequency of this variant in the general population, 0.0000066 (1/152180 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192582	SCV001360813	pathogenic	Hereditary nonpolyposis colon cancer	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.809C>G (p.Ser270X) 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. The variant was absent in 251328 control chromosomes (gnomAD). c.809C>G has been reported in the literature in one individual affected with colorectal cancer, individuals with suspected Lynch syndrome and one individual who had a personal and/or familial history of cancer-most frequently breast, ovarian, or colon (Espenschied_2017, Goodenberger_2015, Rosenthal_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262168	SCV001439941	pathogenic	Lynch syndrome 4	2019-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657645	SCV002019444	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262168	SCV004187733	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	RCV001262168	SCV004203420	pathogenic	Lynch syndrome 4	2021-07-14	criteria provided, single submitter	clinical testing