Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.
Fam Cancer
; 19(4): 315-322, 2020 10.
Article
en En
| MEDLINE
| ID: mdl-32356167
ABSTRACT
Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing. In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant, MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient's tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, the MLH1 c.678-3T>A variant is considered pathogenic.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Intrones
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Neoplasias Colorrectales Hereditarias sin Poliposis
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Mutación de Línea Germinal
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Sitios de Empalme de ARN
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Homólogo 1 de la Proteína MutL
Límite:
Adult
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Aged
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Female
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Humans
Idioma:
En
Revista:
Fam Cancer
Asunto de la revista:
NEOPLASIAS
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos