NM_000314.8:c.143A>C p.(Asn48Thr) is a missense variant in PTEN exon 2.
Mighell et al. 2018 PTEN saturation mutagenesis functional assay demonstrates a damaging effect with a cumulative fitness score of -3.41 (<= -1.11 threshold, High_conf = True), qualifying for PS3_Moderate per the PTEN VCEP v3.2.0.
REVEL score of 0.919 exceeds the VCEP PP3 threshold of >0.7 for missense variants.
PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PP2).
cspec ↗Residue N48 lies outside the VCEP-defined catalytic motifs (90-94, 123-130, 166-168); PM1 is not met.
cspec ↗No de novo observations, segregation data, proband counting data, or alternate molecular basis cases were available for this variant.
clinvar ↗ClinVar reports this variant as Uncertain significance (2 clinical laboratories, variationID 373667).
clinvar ↗Summary of met criteria: PS3_Moderate + PM2_Supporting + PP2 + PP3. Per the PTEN VCEP final classification framework, this combination does not reach the Likely Pathogenic threshold (Rule11 requires PVS1_Strong/PS1/PS2/PS3/PS4/PM6_Strong/PP1_Strong >=1 AND PVS1_Moderate/PS3_Moderate/PS4_Moderate/PM1/PM4/PM5/PM6/PP1_Moderate ==1; Rule13 requires >=3 Moderate criteria). With 1 Moderate (PS3_Moderate) and 3 Supporting (PM2_Supporting, PP2, PP3), the variant remains classified as Uncertain significance.
cspec ↗
