Submissions for variant NM_000057.4(BLM):c.98+1G>C

gnomAD frequency: 0.00003  dbSNP: rs750293380

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826134	SCV000967654	pathogenic	Bloom syndrome	2018-07-18	criteria provided, single submitter	clinical testing	The c.98+1G>C variant in BLM has not been reported individuals with Bloom syndro me, but another variant at the same nucleotide position (c.98+1G>T) has been rep orted in the compound heterozygous state in 1 individual with Bloom syndrome (Ge rman 2007). A third variant at this nucleotide position (c.98+1G>A) has been rep orted to segregate with cancer risk in a single pedigree (de Voer 2015). This va riant has been identified in 7/113042 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750293380). Thi s variant occurs in the invariant region (+/- 1/2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BLM gene is an established disease mechanism in autosomal recessive Bloom syndrome. In summary, the c.98+1G>C variant meets cri teria to be classified as pathogenic for Bloom syndrome in an autosomal recessiv e manner. ACMG/AMP criteria applied: PVS1_Strong, PM5, PM2
Ambry Genetics	RCV001019784	SCV001181188	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-11	criteria provided, single submitter	clinical testing	The c.98+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the BLM gene. This nucleotide position is highly conserved in available vertebrate species. Another alteration at this position (c.98+1G>T) has been reported in a compound heterozygous state in an individual with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). Additionally, another alteration at this position (c.98+1G>A) has been reported in a heterozygous state in an individual with a personal history of early-onset colorectal cancer and a strong family history of colorectal cancer (deVoer RM et al. Sci. Rep. 2015 Sep;5:14060). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000826134	SCV001202279	pathogenic	Bloom syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs750293380, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with Bloom syndrome, colorectal cancer, endometrial cancer, and/or prostate cancer (PMID: 17407155, 26358404, 26689913, 29439820). ClinVar contains an entry for this variant (Variation ID: 667391). Studies have shown that disruption of this splice site results in exon 2 skipping and activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002462193	SCV002010745	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV002462193	SCV002756604	likely pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with colorectal cancer, male breast cancer, ovarian cancer, and endometrial cancer (de Voer 2015, Lu 2015, Koczkowska 2018, Rizzolo 2019); This variant is associated with the following publications: (PMID: 26689913, 26358404, 30441849, 30613976)
Fulgent Genetics, Fulgent Genetics	RCV000826134	SCV002797894	likely pathogenic	Bloom syndrome	2022-04-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000826134	SCV004100700	likely pathogenic	Bloom syndrome	2023-09-27	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_MOD,PP1_MOD,PS1_SUP,PM2_SUP
Baylor Genetics	RCV000826134	SCV004210847	likely pathogenic	Bloom syndrome	2024-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745617	SCV005346153	likely pathogenic	BLM-related disorder	2024-06-12	no assertion criteria provided	clinical testing	The BLM c.98+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in BLM associated disorders. This variant is reported in 0.0061% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/667391/). Variants that disrupt the consensus splice donor site in BLM are expected to be pathogenic. This variant is interpreted as likely pathogenic.