ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.944G>A (p.Arg315Gln) (rs116314131)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163216 SCV000213739 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000524485 SCV000254621 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 315 of the PMS2 protein (p.Arg315Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs116314131, ExAC 0.01%). This variant has been reported in the literature in individuals affected with breast (PMID: 25503501) and ovarian cancer (PMID: 26845104) as well as sarcoma (PMID: 27498913). ClinVar contains an entry for this variant (Variation ID: 184092). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000197131 SCV000266222 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000679365 SCV000279135 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.944G>A at the cDNA level, p.Arg315Gln (R315Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in an individual with history of early-onset breast cancer who also carried a deleterious CHEK2 variant, in an unaffected individual with a family history of ovarian cancer, and in an individual with sarcoma (Maxwell 2015, Ballinger 2016, Shirts 2016). PMS2 Arg315Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg315Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000412322 SCV000487977 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2015-12-07 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000197131 SCV000700120 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 66 year old female with uterine cancer diagnosed at age 56 and a family history of colon cancer. 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.
PreventionGenetics,PreventionGenetics RCV000679365 SCV000806228 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing
Color RCV000163216 SCV000909664 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780629 SCV000918059 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.944G>A (p.Arg315Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like 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 2.2e-05 in 277006 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.944G>A has been reported in the literature in an individual with breast cancer who also carried a pathogenic CHEK2 variant (Maxwell_2014), as well as in a patient with ovarian cancer (Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000412322 SCV001326416 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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