rs375431906
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_000455.5(STK11):c.1036G>A(p.Gly346Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 1,611,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.2303G>A | non_coding_transcript_exon_variant | Exon 9 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.1036G>A | p.Gly346Ser | missense_variant | Exon 8 of 9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.664G>A | p.Gly222Ser | missense_variant | Exon 10 of 12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243724Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132830
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1458890Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5AN XY: 725538
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:3Benign:1
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This missense variant replaces glycine with serine at codon 346 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. This variant has been reported in 2 cases and 4 controls in a large breast cancer association study (PMID: 33471991, https://databases.lovd.nl/). This variant has been identified in 3/243724 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. -
The STK11 c.1036G>A (p.Gly346Ser) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in 2 of 60,466 individuals with breast cancer and in 4 of 53,461 controls (PMID: 33471991). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
not specified Uncertain:3
This variant is denoted STK11 c.1036G>A at the cDNA level, p.Gly346Ser (G346S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Gly346Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly346Ser occurs at a position that is conserved across species and is located in the c-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Gly346Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Variant summary: STK11 c.1036G>A (p.Gly346Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243724 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1036G>A has not been reported in the literature in individuals affected with Peutz-Jeghers Syndrome. However, a recent large-scale breast cancer (BrC) study reported the variant in 2/60466 BrC cases and 4/53461 healthy controls (see Dorling_2021, through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces glycine with serine at codon 346 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 large breast cancer case-control study, this variant has been reported in 2/60466 cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 3/243724 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. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at