NM_000535.7:c.2324A>G
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_000535.7(PMS2):c.2324A>G(p.Asn775Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 169AN: 150216Hom.: 2 Cov.: 30 FAILED QC
GnomAD3 exomes AF: 0.000252 AC: 63AN: 249826Hom.: 3 AF XY: 0.000230 AC XY: 31AN XY: 135022
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000268 AC: 390AN: 1452696Hom.: 24 Cov.: 32 AF XY: 0.000263 AC XY: 190AN XY: 722712
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00112 AC: 169AN: 150318Hom.: 2 Cov.: 30 AF XY: 0.00117 AC XY: 86AN XY: 73352
ClinVar
Submissions by phenotype
Lynch syndrome 4 Benign:6
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
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not specified Benign:5Other:1
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not provided Benign:4
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This variant is associated with the following publications: (PMID: 22949387, 24728327, 22594646, 28347324) -
PMS2: PP2, BS2 -
Hereditary cancer-predisposing syndrome Benign:4
This alteration is classified as 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. -
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Lynch syndrome Uncertain:1Benign:2
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MAF >1% -
Breast and/or ovarian cancer Benign:1
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Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Benign:1
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Lynch syndrome 1 Benign:1
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Hereditary nonpolyposis colorectal neoplasms Benign:1
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Endometrial carcinoma Benign:1
PMS2, Exon14, c.2324A>G, p. Asn775Ser, Benign, ACMG 5 The c.2324A>G variant was identified in 32 of 1428 proband chromosomes (frequency: 0.022) from individuals or families with HNPCC or Lynch syndrome (20698049_sheng_2010, 14756672_Thompson_2004, Clendenning_2006_16619239); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs17420802 ) “With benign allele”, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and the ClinVar database by 7 submitters as benign. The p.Asn775 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn775Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.2324A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at