ClinVar Genomic variation as it relates to human health

Variant summary: The BLM c.1642C>T (p.Gln548X) variant results in a premature termination codon, predicted to cause a truncated or absent BLM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2207_2212delinsTAGATTC). This variant was also found in 27/124630 control chromosomes at a frequency of 0.0002166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). This variant has been reported in three patients with Bloom syndrome, two were known to be compound heterozygotes with another deleterious variant. The variant is also known to confer risk for breast and other types of cancer. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The homozygous p.Gln548Ter variant in BLM was identified by our study in one individual with Bloom syndrome. This variant has been identified in 0.03294% (41/124452) of European (non-Finnish) chromosomes by the Genome Aggregation Databse (gnomAD, http://gnomad.broadinsitute.org; dbSNP rs200389141). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in the literature in the compound heterozygous state, with at least one variant reported pathogenic or likely pathogenic in ClinVar (Variation ID: 127491), in at least three individuals with Bloom syndrome (PMID: 17407155, 23552953). This nonsense variant leads to a premature termination codon at position 548, which is predicted to lead to a truncated or absent protein. Loss of function of the BLM gene is an established disease mechanism for autosomal recessive Bloom syndrome, and this is a loss of function variant. This variant has been reported pathogenic in ClinVar (Variation ID: 127478). In summary, the p.Gln548Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PVS1 (Richards 2015).

This is a nonsense variant that creates a premature stop signal at codon 548 of the BLM protein. It is expected to result in an absent or disrupted protein product. This variant is a common founder mutation among Slavik populations, reported in up to 1% of breast cancer cases in Russia (PMID: 21815139). A meta-analysis study of this mutation has estimated the risk of breast cancer in carriers of this variant to be two to five times higher (PMID: 23225144).

NM_000057.3(BLM):c.1642C>T(Q548*) is classified as pathogenic in the context of Bloom syndrome. Sources cited for classification include the following: PMID 17407155 and 28611551. Classification of NM_000057.3(BLM):c.1642C>T(Q548*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30426508, 29506128, 26689913, 29625052, 26822949, 27153395, 29478780, 25399228, 24096176, 27798748, 23225144, 25410042, 21815139, 25525159, 17407155, 20301572, 26778106, 27597923, 26960971, 28611551, 31159747, 31614901, 31589614, 31937788, 33832920, 33777104, 33219493, 23552953, 32655338)

The BLM c.1642C>T (p.Gln548Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. Loss of function variants in BLM are known to be pathogenic (PMID: 28232778). This variant has a maximum subpopulation frequency of 0.034% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in the homozygous and compound heterozygous state in individuals with Bloom syndrome (PMID: 17407155, 23552953, 26340805, 28611551, 33219493). Studies on breast, ovarian, and prostate cancer patients (PMID: 21815139, 24096176, 25182961, 25399228) have identified this variant in the heterozygous state in both cases and controls. In summary, this variant meets criteria to be classified as pathogenic

This sequence change creates a premature translational stop signal (p.Gln548*) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant is present in population databases (rs200389141, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome, breast cancer, colorectal cancer, and/or prostate cancer (PMID: 17407155, 23225144, 23552953, 24096176, 25399228, 26358404). It is commonly reported in individuals of Slavic ancestry (PMID: 23225144, 24096176). ClinVar contains an entry for this variant (Variation ID: 127478). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

The p.Q548* pathogenic mutation (also known as c.1642C>T), located in coding exon 6 of the BLM gene, results from a C to T substitution at nucleotide position 1642. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been identified in the homozygous and compound heterozygous state with another pathogenic BLM mutation in multiple individuals with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53; Classen CF et al. Hum. Genet. 2013 Jul;132:825-41; Suspitsin EN et al. Mol Syndromol 2017 Mar;8(2):103-106). It has also been identified in the heterozygous state in individuals with breast cancer, prostate cancer, and colorectal cancer and is considered a possible Slavic founder mutation (Sokolenko AP et al. Int. J. Cancer. 2012 Jun;130:2867-73; Prokofyeva D et al. Breast Cancer Res. Treat. 2013 Jan;137:533-9; Lhota F et al. Clin. Genet. 2016 Oct;90:324-33; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; deVoer RM et al. Sci Rep 2015 Sep;5:14060; Antczak A et al. Gene 2013 Dec;532(2):173-6). One case-control study in Poland identified this mutation in 82/14804 unselected breast cancer cases and 26/4698 cancer-free women (Kluzniak W et al. Cancers (Basel) 2019 Oct;11(10)). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bloom syndrome (MIM#210900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (46 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many individuals with Bloom syndrome in a homozygous or compound heterozygous state (ClinVar, PMIDs: 28611551, 32655338). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The BLM c.1642C>T (p.Gln548Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Gln548Ter variant has been identified in a total of eight individuals with Bloom syndrome, including in four in a homozygous state and in four in a compound heterozygous state (German et al. 2007; Classen et al. 2013; Vojtková et al. 2016; Suspitsin et al. 2017). The compound heterozygotes all carry a second null variant in trans including one deletion, one splice variant and two stop-gained variants. The p.Gln548Ter variant was found to segregate with disease in a two generation family. The p.Gln548Ter variant was reported in a heterozygous state in 32 of 8809 controls and is noted to be a founder variant in the Slavic population (Antczak et al. 2013; Bogdanova et al. 2015). The variant is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln548Ter variant is classified as pathogenic for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The p.Gln548X variant in BLM has been reported in at least 5 individuals with Bloom syndrome (2 homozygotes and 3 compound heterozygotes) and segregated with disease in at least 2 affected relatives from 1 family (German 2007 PMID: 17407155, Vojtkova 2016 PMID: 26340805, Suspitsin 2017 PMID: 28611551). In the heterozygous state, this variant is associated with an increased risk for developing breast cancer, particularly in the Slavic population (Sokolenko 2012 PMID: 21815139, Prokofyeva 2013 PMID: 23225144), although another study does not support its role as a susceptibility factor in breast cancer (Asiminenko 2014 PMID: 25399228). Additionally, this variant has also been reported by other clinical laboratories in ClinVar (Variation ID 127478) and has also been identified in 0.03% (43/126942) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This nonsense variant leads to a premature termination codon at position 548, which is predicted to lead to a truncated or absent protein. Loss of function of the BLM gene is an established disease mechanism in autosomal recessive Bloom syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Bloom syndrome. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1.

This nonsense variant causes the premature termination of BLM protein synthesis. The frequency of this variant in the general population, 0.000339 (43/126942 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26822949 (2016), 25399228 (2014)), ovarian cancer (PMID: 25182961 (2015)), prostate cancer (PMID: 32923906 (2020), 24096176 (2013)), and colorectal cancer (PMID: 26358404 (2015)). The variant has been detected in individuals with Bloom Syndrome where individuals were compound heterozygous for the variant and a BLM pathogenic or likely pathogenic variant (PMID: 28611551 (2017), 26340805 (2016), 17407155 (2005). In addition, this variant has been reported as a Slavic founder mutation in individuals with breast cancer (PMID: 23225144 (2013), 21815139 (2012)). Based on the available information, this variant is classified as pathogenic.

BLM: PVS1, PM3:Strong, PM2

The variant BLM:c.1642C>T p.(Gln548*), which is located in the coding exon 7 of the BLM gene, results from a cytosine to thymine substitution at nucleotide position 1642. The glutamine at protein position 548 is replaced by a stop codon at the translational level. The variant affects and exon (7/22) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay in a gene where loss of function is a known mechanism of disease. The variant is classified as very rare in the overall population (allele frequency= 0.00017 in gnomAD v4.1.0). The variant has already been described in homozygous as well as compound heterozygous state in patients affected with BLM-associated disorders (PMID: 17407155, 23552953, 26340805, 28611551, 33219493). In summary, the variant is classified as Pathogenic.

The BLM c.1642C>T variant is predicted to result in premature protein termination (p.Gln548*). This variant has been reported in multiple individuals with Bloom syndrome (Table 1, German et al. 2007. PubMed ID: 17407155; Suspitsin et al. 2017. PubMed ID: 28611551). It has been reported as a common founder variant in Slavic populations (Sokolenko et al. 2012. PubMed ID: 21815139; Prokofyeva et al. 2013. PubMed ID: 23225144). This variant is reported in 0.034% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127478/). Nonsense variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic.