Submissions for variant NM_000535.7(PMS2):c.1096G>C (p.Asp366His)

gnomAD frequency: 0.00003  dbSNP: rs141769057

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586764	SCV000149558	uncertain significance	not provided	2022-12-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals with breast and uterine cancer (Maxwell et al., 2015; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 25503501, 27181684, 29684080, 31391288, 31422818, 33471991)
Invitae	RCV001085405	SCV000254593	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220170	SCV000273033	likely benign	Hereditary cancer-predisposing syndrome	2020-12-15	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586764	SCV000601806	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 25503501 (2015), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/genes/BRCA1)) and colorectal cancer (PMID: 31391288 (2020)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/genes/BRCA1)). The frequency of this variant in the general population, 0.000011 (3/282614 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000115649	SCV000697278	uncertain significance	not specified	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1096G>C (p.Asp366His) results in a non-conservative amino acid change in 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 8e-06 in 251216 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096G>C has been reported in the literature in individuals affected with Lynch syndrome and related cancers, as well as those affected with breast cancer (example, Maxwell_2014, Li_2020, Dorling_2021), though it was also detected in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25503501, 31391288, 31422818, 33471991). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as likely benign and four classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000590932	SCV000700133	uncertain significance	Lynch syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 30 year old male diagnosed with colon cancer at age 30. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000115649	SCV000711440	uncertain significance	not specified	2017-04-03	criteria provided, single submitter	clinical testing	The p.Asp366His variant in PMS2 has been previously identified in at least 1 in dividual with early onset breast cancer who had tested negative for variants in BRCA1 and 2 (Maxwell 2015). This variant has also been identified in 1/8654 of E ast Asian chromosomes and 1/11578 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs141769057). Asparagin e (Asp) at position 366 is not conserved in mammals or evolutionarily distant sp ecies and the change to histidine (His) is present in 2 turtle species, suggesti ng this change may be tolerated. Additional computational prediction tools do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Asp366His variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000220170	SCV000902928	likely benign	Hereditary cancer-predisposing syndrome	2016-02-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315638	SCV004018671	likely benign	Lynch syndrome 4	2023-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.