Submissions for variant NM_000455.5(STK11):c.464+5G>A

gnomAD frequency: 0.00002  dbSNP: rs587781681

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129842	SCV000184659	likely benign	Hereditary cancer-predisposing syndrome	2022-03-22	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.
GeneDx	RCV000986037	SCV000566638	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 15863673)
Invitae	RCV000537602	SCV000629117	likely benign	Peutz-Jeghers syndrome	2024-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129842	SCV000686655	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 3 of the STK11 gene. Splice site prediction tools predict that this variant may impact RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/218862 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.
Fulgent Genetics, Fulgent Genetics	RCV000765430	SCV000896714	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986037	SCV001134842	uncertain significance	not provided	2018-10-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000986037	SCV001151577	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000986037	SCV001477576	uncertain significance	not provided	2020-02-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000537602	SCV002057800	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149895	SCV003837865	uncertain significance	Breast and/or ovarian cancer	2023-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526619	SCV005039730	likely benign	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.464+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-05 in 1576020 control chromosomes. The observed variant frequency is approximately 3.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.464+5G>A has been reported in the literature as a VUS in settings of multigene panel testing in an individual with a personal and family history of Breast and/or Colorectal cancer (example, de Oliveira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 141354). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355662	SCV001550610	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 c.464+5G>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587781681) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae and Color Genomics Inc.), Clinvitae (3x), and in control databases in 5 of 213708 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population includes European Non-Finnish in 5 of 93184 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in a case along with a co-occurring pathogenic variant in BRCA2 (c.9097dupA, p.Thr3033AsnfsX11). The c.464+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.