Submissions for variant NM_000535.7(PMS2):c.71A>C (p.His24Pro)

gnomAD frequency: 0.00005  dbSNP: rs139233015

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166828	SCV000217642	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.H24P variant (also known as c.71A>C), located in coding exon 2 of the PMS2 gene, results from an A to C substitution at nucleotide position 71. The histidine at codon 24 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000459353	SCV000552044	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 24 of the PMS2 protein (p.His24Pro). This variant is present in population databases (rs139233015, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000166828	SCV000686230	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 24 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/277116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588792	SCV000697379	uncertain significance	not specified	2020-11-04	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.71A>C (p.His24Pro) results in a non-conservative amino acid change located in the N-terminal DNA mismatch repair domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.71A>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001293982	SCV001482723	uncertain significance	Lynch syndrome 4	2020-08-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001594864	SCV001828026	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000166828	SCV004014959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing