ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1096G>C (p.Asp366His) (rs141769057)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586764 SCV000149558 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1096G>C at the cDNA level, p.Asp366His (D366H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been reported at least one individual with early-onset breast cancer with previously negative BRCA1/2 analysis (Maxwell 2015). PMS2 Asp366His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Asp366His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001085405 SCV000254593 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000220170 SCV000273033 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing The p.D366H variant (also known as c.1096G>C), located in coding exon 10 of the PMS2 gene, results from a G to C substitution at nucleotide position 1096. The aspartic acid at codon 366 is replaced by histidine, an amino acid with similar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586764 SCV000601806 uncertain significance not provided 2020-01-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000115649 SCV000697278 uncertain significance not specified 2020-11-10 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 (gnomAD). 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 one individual affected with breast cancer (Maxwell_2014) and one individual affected with Lynch syndrome and related cancers (Li_2020). 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (5x) and likely benign (2x). 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,Partners HealthCare 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 Health, Inc RCV000220170 SCV000902928 likely benign Hereditary cancer-predisposing syndrome 2016-02-29 criteria provided, single submitter clinical testing

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