PMS2 c.779C>T, p.Ser260Phe
NM_000535.7:c.779C>T
Variant of Uncertain Significance (VUS)
The variant p.Ser260Phe in PMS2 receives only two supporting benign criteria (BP1, BP4) and no pathogenic criteria. Insufficient evidence of pathogenicity or strong benign evidence leads to a final classification of VUS.
ACMG/AMP Criteria Applied
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
PMS2
Transcript
NM_000535.7
MANE Select
Total Exons
15
Strand
Reverse (−)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 15 exons | Reverse |
| NM_000535.4 | Alternative | 15 exons | Reverse |
| NM_000535.3 | Alternative | 15 exons | Reverse |
| NM_000535.5 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_000535.7:c.779C>T
Protein Change
S260F
Location
Exon 7
(Exon 7 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 260 in gene PMS2
Variant interpretation based on transcript NM_000535.7
Genome Browser
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HGVS InputNM_000535:c.779C>T
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Clinical Data
Global Frequency
0.0177%
Low Frequency
Highest in Population
South Asian
0.157%
Common
Global: 0.0177%
South Asian: 0.157%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282054Alt: 50Homozygotes: 1
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0177%, 50/282054 alleles, homozygotes = 1) and at a higher frequency in the South Asian population (MAF= 0.157%, 48/30522 alleles, homozygotes = 1). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The PMS2 c.779C>T (p.Ser260Phe) variant has been reported in the published literature in an individual with breast cancer (PMID: 35449176 (2022)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 260 in gene PMS2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.50metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong: Nonsense/frameshift variant introducing a premature termination codon or splice site variants expected to undergo NMD." The evidence for this variant shows it is a missense change (p.Ser260Phe). Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change as a previously established pathogenic variant." The evidence for this variant shows no previously established pathogenic variant results in p.Ser260Phe. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong/Strong/Moderate/Supporting based on de novo points." The evidence for this variant shows no data on de novo occurrence or parental testing. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7." The evidence for this variant shows no functional studies are available. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows no case-control or patient cohort data. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well‐studied functional domain without benign variation." The evidence for this variant shows no data placing codon 260 in a recognized hotspot or critical domain. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent or extremely rare (<1 in 50,000 alleles) in gnomAD." The evidence for this variant shows a maximum population MAF of 0.0177% (1 in ~5,650 alleles), exceeding the 0.002% threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting: Observed in trans with a pathogenic variant in a recessive disorder." The evidence for this variant shows no observation of the variant in trans in a recessive context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows it is a missense change without length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change has been classified as pathogenic by this VCEP." The evidence for this variant shows no other pathogenic missense variant at codon 260. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting: De novo occurrence without confirmation of parental identity." The evidence for this variant shows no de novo or parental data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members." The evidence for this variant shows no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with a low rate of benign missense variation." The evidence for this variant shows PMS2 does not have a well‐established low benign missense variation metric. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Moderate: Missense variant with HCI prior >0.81 or SpliceAI delta ≥0.2." The evidence for this variant shows SpliceAI delta=0.01 and no high HCI prior. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Strong: ≥3 independent CRC/Endometrial MSI-H tumors or consistent loss of MMR protein." The evidence for this variant shows no tumor or IHC data. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic." The evidence for this variant shows ClinVar reports it as VUS. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD v4 MAF ≥0.28%." The evidence for this variant shows MAF=0.0177%, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: gnomAD v4 MAF ≥0.01% and <0.1%." The evidence for this variant shows a maximum MAF of 0.157% in South Asians, exceeding 0.1%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed in trans with a pathogenic variant in a healthy adult." The evidence for this variant shows no such co-occurrence data. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Calibrated functional assays showing no functional impact (odds ≤0.05)." The evidence for this variant shows no functional assays. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Strong: Lack of co-segregation in affected family members." The evidence for this variant shows no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in a gene where truncating variants are the known mechanism of disease." The evidence for this variant shows PMS2 disease mechanism is loss-of-function and this is a missense change. Therefore, BP1 is applied at Supporting strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows no such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indel in a repetitive region without known function." The evidence for this variant shows it is a missense change. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: SpliceAI predicts no impact with delta ≤0.1 or MAPP/PP2 prior <0.11." The evidence for this variant shows SpliceAI delta=0.01 indicating no splicing impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting: Tumor data showing inconsistent loss of MMR protein on tumors with MSS or BRAF/MLH1 methylation patterns." The evidence for this variant shows no tumor data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign." The evidence for this variant shows ClinVar reports it as VUS. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variant without splicing impact." The evidence for this variant shows it is missense. Therefore, BP7 is not applied.