ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.921-10G>A (rs183406870)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000128300 SCV000171892 benign not specified 2014-05-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000200730 SCV000253266 benign Peutz-Jeghers syndrome 2020-11-30 criteria provided, single submitter clinical testing
Counsyl RCV000200730 SCV000488016 likely benign Peutz-Jeghers syndrome 2015-12-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000128300 SCV000602242 benign not specified 2020-03-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000579573 SCV000686704 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000128300 SCV000920283 benign not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: STK11 c.921-10G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 178932 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 166.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Hereditary Breast and Ovarian Cancer phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.921-10G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.3261delC), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357217 SCV001552611 likely benign not provided no assertion criteria provided clinical testing The STK11 c.921-10G>A variant was identified as a somatic change in 1 of 114 proband chromosomes (frequency: 0.009) from an individual with adenocarcinoma of the cervix (Kuragaki 2003). The variant was also identified in the following databases: dbSNP (ID: rs183406870) as "With Likely benign allele", ClinVar (3x likely benign, 2x benign), Clinvitae, and Cosmic (1x, confirmed somatic, in tumour of the cervix). The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 32 of 178932 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 32 of 12228 chromosomes (freq: 0.003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The c.921-10G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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