Submissions for variant NM_000535.7(PMS2):c.708G>T (p.Leu236Phe)

dbSNP: rs201395630

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165656	SCV000216393	likely benign	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231924	SCV000285149	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000412437	SCV000489520	uncertain significance	Lynch syndrome 4	2016-10-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000034634	SCV000565388	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with kidney cancer and in an individual with cancer evaluated with MSI and IHC (Yehia et al., 2018; Li et al., 2020); This variant is associated with the following publications: (PMID: 22703879, 28569743, 29684080, 29570743, 32277576, 31391288, 11574484, 27600092)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290448	SCV000697378	uncertain significance	not specified	2022-09-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.708G>T (p.Leu236Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 184566 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.708G>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or other type of cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165656	SCV000911382	likely benign	Hereditary cancer-predisposing syndrome	2016-01-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000412437	SCV001137317	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412437	SCV004019886	uncertain significance	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000412437	SCV004205507	uncertain significance	Lynch syndrome 4	2024-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042107	SCV005674346	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2024-04-22	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034634	SCV000043434	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.