ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1488C>T (p.His496=) (rs1805320)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076812 SCV000108298 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Ambry Genetics RCV000128937 SCV000172811 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174012 SCV000225234 benign not specified 2018-03-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000174012 SCV000304720 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625503 SCV000469731 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-02-02 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000756560 SCV000562225 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128937 SCV000686129 benign Hereditary cancer-predisposing syndrome 2015-04-22 criteria provided, single submitter clinical testing
Counsyl RCV000625503 SCV000785327 benign Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282357 SCV000884398 benign none provided 2020-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000174012 SCV000691972 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000625503 SCV000745843 benign Hereditary nonpolyposis colorectal cancer type 4 2016-01-22 no assertion criteria provided clinical testing
True Health Diagnostics RCV000128937 SCV000788102 likely benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354144 SCV001548686 benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.His496= variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs1805320) as “with benign allele” and ClinVar (classified as benign by Ambry Genetics, Color, Invitae, Counsyl and 6 other submitters; and as likely benign by True Health Diagnostics and Illumina). The variant was identified in control databases in 2168 of 282,774 chromosomes (70 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1934 of 24,924 chromosomes (freq: 0.08), Latino in 163 of 35,440 chromosomes (freq: 0.005), Other in 22 of 7220 chromosomes (freq: 0.003), South Asian in 10 of 30,616 chromosomes (freq: 0.0003), European in 36 of 129,170 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10,368 chromosomes (freq: 0.0001), East Asian in 1 of 19,946 chromosomes (freq: 0.00005), and Finnish in 1 of 25,090 chromosomes (freq: 0.00004). The variant was observed with a co-occurring, pathogenic PMS2 variant (p.SerGlyfs*3) in an individual with colorectal cancer (Nomura 2015), decreasing the likelihood that this variant has clinical significance. The p.His496= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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