Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1
The NM_000535.7(PMS2):c.1242C>T(p.Asp414Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 7-5987523-G-A is Benign according to our data. Variant chr7-5987523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 187191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.692 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000243 (37/152278) while in subpopulation AFR AF= 0.00077 (32/41564). AF 95% confidence interval is 0.00056. There are 1 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jun 08, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
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Dec 08, 2014
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: 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. -
not specified Benign:2
Dec 24, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jun 24, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Benign:2
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
The PMS2 p.Asp414= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142839559) as "With Likely benign allele" and in ClinVar (classified as benign by Invitae; and as likely benign by Ambry Genetics, Color and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 37 of 277098 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24012 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 6 of 34414 chromosomes (freq: 0.0002), and European in 2 of 126636 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp414= 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. In addition, 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Lynch syndrome Benign:1
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter