7-6003788-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_000535.7(PMS2):c.255G>A(p.Leu85Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,600,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000535.7 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000177 AC: 43AN: 243496Hom.: 0 AF XY: 0.000196 AC XY: 26AN XY: 132814
GnomAD4 exome AF: 0.000188 AC: 273AN: 1448570Hom.: 0 Cov.: 28 AF XY: 0.000213 AC XY: 154AN XY: 721582
GnomAD4 genome AF: 0.000112 AC: 17AN: 152060Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74270
ClinVar
Submissions by phenotype
not provided Benign:5
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PMS2: BP4 -
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not specified Benign:4
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Hereditary cancer-predisposing syndrome Benign:4
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. -
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Lynch syndrome 4 Benign:3
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This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Breast and/or ovarian cancer Benign:1
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Lynch syndrome Benign:1
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Hereditary nonpolyposis colorectal neoplasms Benign:1
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Endometrial carcinoma Benign:1
The PMS2 p.Leu85= variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs200491279) “With Likely benign allele”, ClinVar (as benign by GeneDx, and likely benign by Ambry Genetics, Invitae and Color Genomics Inc.), Clinvitae (3x), and in control databases in 49 of 269350 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017) being identified in the following populations: Other in 1 of 6368 chromosomes (frequency: 0.0002), Latino in 2 of 34332 chromosomes (frequency: 0.00006), European Non-Finnish in 45 of 123320 chromosomes (frequency: 0.0004) and in South Asian in 1 of 30744 chromosomes (frequency: 0.00003). The p.Leu85 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, HumanSpliceFinder) 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at