Submissions for variant NM_000455.5(STK11):c.1244G>A (p.Arg415His)

dbSNP: rs775978755

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000551966	SCV000629084	likely benign	Peutz-Jeghers syndrome	2023-12-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568457	SCV000676283	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The p.R415H variant (also known as c.1244G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1244. The arginine at codon 415 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported with a carrier frequency of 1 in 7051 unselected breast cancer patients and 0 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568457	SCV001342219	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 415 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/171592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000551966	SCV002057987	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002305502	SCV002599675	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28900777, 30287823)
Baylor Genetics	RCV003459197	SCV004205558	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-09-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002305502	SCV004221270	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 30287823 (2018)) and colorectal cancer (PMID: 33020649 (2020)). This variant has also been reported as a somatic variant in an individual with lung cancer (PMID: 30885352 (2019)). The frequency of this variant in the general population, 0.00012 (1/171592 chromosomes (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.