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 ↗

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

KRAS NM_001369787.1

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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