Variant normalization failed: Mutalyzer returned HTTP 422, and VariantValidator reported a ReferenceMismatchError (reference base at NM_000546.6:c.370 is T, not C). The gene, protein consequence, and genomic coordinates could not be resolved. PVS1 is not applicable — NM_000546.6:c.370C>T is a substitution variant, not a null variant eligible for PVS1 consideration. All other criteria could not be assessed. Population databases (gnomAD v2.1, v4.1), ClinVar, in silico predictors (REVEL, BayesDel, SpliceAI), functional databases (COSMIC, OncoKB, Hotspots), and the published literature returned no usable evidence for this variant because gene/coordinate lookup prerequisites were not met. No classification can be assigned. The variant cannot be evaluated under ACMG/AMP 2015 criteria without successful normalization. Manual review is required: confirm the correct HGVS expression (NM_000546.6:c.370C>T may have an incorrect reference base), re-run normalization, and re-attempt all evidence gathering.
Final classification
VUS
c.370C>T
Variant normalization failed: Mutalyzer returned HTTP 422, and VariantValidator reported a ReferenceMismatchError (reference base at NM_000546.6:c.370 is T, not C). The gene, protein consequence, and genomic coordinates could not be resolved.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
Classification rationale
VUS
c.370C>T
Applied criteria · 0 applied · 24 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PS1
Cannot assess.
PS2
Cannot assess.
PS3
Cannot assess.
PS4
Cannot assess.
PM1
Cannot assess.
PM2
Cannot assess.
PM5
Cannot assess.
PM6
Cannot assess.
PP1
Cannot assess.
PP2
Cannot assess.
PP3
Cannot assess.
PP4
Cannot assess.
PP5
Cannot assess.
Benign
BA1
Cannot assess.
BS1
Cannot assess.
BS2
Cannot assess.
BS3
Cannot assess.
BS4
Cannot assess.
BP1
Cannot assess.
BP2
Cannot assess.
BP4
Cannot assess.
BP5
Cannot assess.
BP6
Cannot assess.
BP7
Cannot assess.
N/A · 1
PVS1
Research & evidence
Population frequency
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
No data
No ClinVar submissions were recorded for this variant.
In silico
No data
No in-silico prediction was recorded for this variant.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
No sources recorded.