Classification rationale

BA1BP6 Benign

KRAS c.519T>C

The KRAS c.519T>C (p.Asp173=; p.D173=) variant has been reported in ClinVar as Benign, including by the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is common in population databases, with an allele frequency of 19.06% in gnomAD v2.1 and 20.60% in gnomAD v4.1, which is far above the KRAS RASopathy VCEP BA1 benign threshold of 0.05%.² In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.10.³

BA1 + BP6 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001369787.1 · variants mapped to exon structure

KRAS NM_001369787.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This synonymous KRAS variant is present at a population frequency far above the benign stand-alone threshold. In gnomAD, the allele frequency is 19.06% in v2.1 and 20.60% in v4.1, which is well above the KRAS RASopathy VCEP BA1 threshold of 0.05%.

gnomAD v2.1 total AF 0.190556 (53595/281256 alleles

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

KRAS RASopathy VCEP applicability tableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant.

PS3 No approved variant-specific functional assay evidence was identified for this synonymous KRAS variant.

PS4 Available evidence does not support enrichment in affected individuals.

PM1 This variant does not fall within the KRAS RASopathy VCEP PM1 functional domain ranges of amino acids 10-17, 25-40, 57-64, or 145-156.

PM2 This variant is not absent from controls.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect.

Benign

BS1 Population frequency also exceeds the BS1 threshold, but BA1 is already met and is the more appropriate population rule for this variant.

BS2 This variant is common in population databases, including many homozygotes, but no phenotype-linked adult observation data were identified to assign the KRAS RASopathy VCEP BS2 point-based rule directly.

BS4 No family data showing lack of segregation were identified for this variant.

BP2 No phase data or point-based evidence for occurrence with another causative variant were identified for this variant.

BP5 No evidence was identified for an alternative molecular explanation or phenotype inconsistency meeting the KRAS RASopathy VCEP point-based BP5 rule.

BP7 This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.

N/A · 12 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP4

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.205996; MAF= 20.59958%, 331554/1609518 alleles, homozygotes = 34745) and has highest observed frequency in the Amish population (AF= 0.395604; MAF= 39.56044%, 360/910 alleles, homozygotes = 72); grpmax FAF= 0.226615.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.190556; MAF= 19.05559%, 53595/281256 alleles, homozygotes = 5310) and has highest observed frequency in the European (non-Finnish) population (AF= 0.221247; MAF= 22.12469%, 28382/128282 alleles, homozygotes = 3073); grpmax FAF= 0.220075.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

21% · 331554 / 1,609,518
34745 hom · FAF 23%

Amish 360 / 910	40% 72 hom
Middle Eastern 1429 / 6,034	24% 188 hom
European (non-Finnish) 255635 / 1,176,612	22% 27665 hom
Remaining individuals 12556 / 62,338	20% 1264 hom
South Asian 17509 / 90,800	19% 1865 hom
Admixed American 10788 / 59,890	18% 998 hom
African/African American 13176 / 74,860	18% 1190 hom
Ashkenazi Jewish 4811 / 29,538	16% 382 hom
European (Finnish) 10201 / 63,850	16% 830 hom
East Asian 5089 / 44,686	11% 291 hom

gnomAD v2.1

19% · 53595 / 281,256
5310 hom · FAF 22%

European (non-Finnish) 28382 / 128,282	22% 3073 hom
Remaining individuals 1470 / 7,172	20% 144 hom
South Asian 5808 / 30,436	19% 597 hom
African/African American 4373 / 24,844	18% 378 hom
Admixed American 6048 / 35,250	17% 554 hom
Ashkenazi Jewish 1696 / 10,336	16% 129 hom
European (Finnish) 3924 / 25,032	16% 341 hom
East Asian 1894 / 19,904	9.5% 94 hom

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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