ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1812del (p.Ala605fs) (rs80357927)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166934 SCV000217753 pathogenic Hereditary cancer-predisposing syndrome 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA1) RCV000111690 SCV000144191 pathogenic Breast-ovarian cancer, familial 1 2001-10-29 no assertion criteria provided clinical testing
Color RCV000166934 SCV000905035 pathogenic Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111690 SCV000325146 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111690 SCV000299650 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000159902 SCV000210015 pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing This deletion of one nucleotide is denoted BRCA1 c.1812delA at the cDNA level and p.Ala605HisfsX7 (A605HfsX7) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 1931delA. The normal sequence, with the base that is deleted in brackets, is CAAA[delA]GCAC. The deletion causes a frameshift, which changes an Alanine to a Histidine at codon 605, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1812delA has been observed in at least one individual with a personal history of breast and colon cancer (Susswein 2016). We considered this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000204705 SCV000918682 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1812delA (p.Ala605HisfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.1823_1826delAGAA (p.Lys608fsX3), c.1874_1877dupTAGT (p.Val627fsX4), and c.1938_1947delCAGTGAAGAG (p.Ser646fsX2)). The variant was absent in 121068 control chromosomes (ExAC). A publication, Susswein_2016 cites the variant in an affected individual with a clinical history of breast and colon cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic," along with multiple reputable databases. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000204705 SCV000259696 pathogenic Hereditary breast and ovarian cancer syndrome 2015-07-31 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the BRCA1 mRNA (c.1812delA), causing a frameshift at codon 605. This creates a premature translational stop signal (p.Ala605Hisfs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). This variant is also known as 1931delA. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000204705 SCV000271312 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Ala605fs variant in BRCA1 has been reported in 1 individual with breast an d colon cancer (Susswein 2015). It was absent from large population studies, tho ugh the ability of these studies to accurately detect indels may be limited. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 605 and leads to a premature termination codo n 7 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. Heterozygous loss of function of the BRCA1 gene is an es tablished disease mechanism for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for auto somal dominant HBOC.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159902 SCV000888848 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing

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