Submissions for variant NM_000455.5(STK11):c.1147C>T (p.Arg383Cys)

gnomAD frequency: 0.00001  dbSNP: rs535449626

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131320	SCV000186293	likely benign	Hereditary cancer-predisposing syndrome	2024-06-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168106	SCV000218762	likely benign	Peutz-Jeghers syndrome	2025-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131320	SCV001354160	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 383 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). 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, but has been observed in control individuals (PMID: 32980694, 30287823). This variant has been identified in 3/241446 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255473	SCV001431890	uncertain significance	not specified	2024-03-24	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1147C>T (p.Arg383Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 263928 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although observed in the literature (example, Momozawa_2018), to our knowledge, no occurrence of c.1147C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 142289). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000168106	SCV002057944	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584354	SCV002577874	uncertain significance	See cases	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PP3
All of Us Research Program, National Institutes of Health	RCV000168106	SCV004818993	uncertain significance	Peutz-Jeghers syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 383 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, but has been observed in control individuals (PMID: 32980694, 30287823). This variant has been identified in 3/241446 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.
GeneDx	RCV004721272	SCV005327556	uncertain significance	not provided	2024-02-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with prostate cancer (PMID: 36095024); This variant is associated with the following publications: (PMID: 30287823, 28900777, 36243179, 32980694, 36095024)