Submissions for variant NM_000455.5(STK11):c.1108G>A (p.Gly370Arg)

dbSNP: rs747655835

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165481	SCV000216212	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	The c.1108G>A variant (also known as p.G370R), located in coding exon 8 of the STK11 gene, results from a G to A substitution at nucleotide position 1108. The amino acid change results in glycine to arginine at codon 370, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in multiple individuals with no reported features of Peutz-Jeghers syndrome (PJS) (Ambry internal data). This variant has been reported in 1 in 7051 unselected breast cancer patients and 0 of 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This nucleotide position is highly conserved on sequence alignment. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000199120	SCV000254539	uncertain significance	Peutz-Jeghers syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 370 of the STK11 protein (p.Gly370Arg). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 185965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000165481	SCV001351984	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 370 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 reported for this variant. In a case-control study conducted in Japan, this variant was reported in 1/7051 female breast cancer cases and absent in 11241 controls (PMID: 30287823). This variant has not been identified 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	RCV000199120	SCV002057930	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468745	SCV004205599	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2024-01-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000199120	SCV004818988	uncertain significance	Peutz-Jeghers syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 370 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 reported for this variant. In a case-control study conducted in Japan, this variant was reported in 1/7051 female breast cancer cases and absent in 11241 controls (PMID: 30287823). This variant has not been identified 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.