Submissions for variant NM_000057.4(BLM):c.3210+2del

gnomAD frequency: 0.00003  dbSNP: rs587779886

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628687	SCV000749593	likely pathogenic	Bloom syndrome	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 16 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 (rs587779886, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with mesothelioma (PMID: 26556299, 29439820). ClinVar contains an entry for this variant (Variation ID: 127497). Studies have shown that disruption of this splice site results in skipping of exon 16 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000628687	SCV000918655	likely pathogenic	Bloom syndrome	2023-01-20	criteria provided, single submitter	clinical testing	Variant summary: BLM c.3210+2delT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 216206 control chromosomes (gnomAD). c.3210+2delT has been reported in the literature in individuals affected with prostate cancer (Antonarakis_2018, Ledet_2020) and mesothelioma (Schrader _2016). In these individuals, a second pathogenic variant has not been reported. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) classify the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001019262	SCV001180594	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-28	criteria provided, single submitter	clinical testing	The c.3210+2delT intronic variant, located in intron 15 of the BLM gene, results from a deletion of one nucleotide within intron 15 of the BLM gene. This variant has been detected in a metastatic prostate cancer patients (Antonarakis ES et al. Eur Urol. 2018 Aug;74(2):218-225; Ledet EM et al. Prostate, 2020 02;80:235-237). This variant has also been observed in individuals affected with mesothelioma (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Fulgent Genetics, Fulgent Genetics	RCV000628687	SCV002781919	likely pathogenic	Bloom syndrome	2022-04-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000628687	SCV003820333	likely pathogenic	Bloom syndrome	2022-11-30	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000628687	SCV003843036	uncertain significance	Bloom syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The BLM c.3210+2del intronic change results in the deletion of one nucleotide in intron 16 of the BLM gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product. This variant has been reported in at least one individual with metastatic prostate cancer (PMID: 29439820, 31816118) and in individuals with mesothelioma (PMID: 26556299). It has a maximum subpopulation frequency of 0.0010% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in individuals with Bloom syndrome.  In summary, this variant meets criteria to be classified as likely pathogenic.
Baylor Genetics	RCV000628687	SCV004210838	likely pathogenic	Bloom syndrome	2023-10-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000628687	SCV002090526	likely pathogenic	Bloom syndrome	2017-08-16	no assertion criteria provided	clinical testing