NM_007294.4:c.3328_3330delAAG
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6
The NM_007294.4(BRCA1):c.3328_3330delAAG(p.Lys1110del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,612,992 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007294.4 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000396 AC: 99AN: 250222Hom.: 1 AF XY: 0.000583 AC XY: 79AN XY: 135406
GnomAD4 exome AF: 0.000175 AC: 256AN: 1460900Hom.: 1 AF XY: 0.000283 AC XY: 206AN XY: 726756
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74292
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:5
See Variant Classification Assertion Criteria. -
The BRCA1 c.3328_3330delAAG; p.Lys1110del variant (rs80358335) is reported in the literature in individuals with breast and/or ovarian cancer (Ahmad 2012, Mannan 2016, Mehta 2018), and is reported in ClinVar (Variation ID: 54840). This variant is found in the South Asian population with an allele frequency of 0.3% (99/30598 alleles, including 1 homozygote) in the Genome Aggregation Database. The lysine at codon 1110 is not highly conserved and does not occur in a known functional domain. Additionally, at least one functional study shows this variant is able to complement the growth defect of BRCA1 null cells, suggesting the variant does not impair BRCA1 function (Bouwman 2013). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Ahmad J et al. Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. Clin Genet. 2012 Dec;82(6):594-8. Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Mannan AU et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet. 2016 Jun;61(6):515-22. Mehta A et al. Germline BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India. Cancer Manag Res. 2018 Nov 30;10:6505-6516. -
BRCA1: PM4:Supporting, BS3:Supporting, BS2 -
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The BRCA1 p.Lys1110del variant was identified in at least 1 of 55630 proband chromosomes from individuals or families with breast or ovarian cancer (Judkins 2005). The variant was also identified in dbSNP (ID: rs80358335) “With Uncertain significance allele”, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 54 of 121128 chromosomes (frequency: 0.0004), or 54 individuals from a population of South Asian individuals, and none from European (Non-Finnish), East Asian, Other, African, Latino, or European (Finnish) individuals; and the ClinVar database (classified as a variant with uncertain significance by BIC, Ambry Genetics and Molecular Genetics Diagnostic Laboratory, CHEO and classification not provided by Invitae), and GeneInsight COGR database(3X, classified as “unknown significance” by 2 clinical laboratories, and unclassified by another). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 1110; however, the impact of this alteration on BRCA1 protein function is not known. A cDNA-based functional complementation assay using BRCA1-deficient mouse embryonic stem cells, classified the variant as neutral by restoring cell proliferation and showing cisplatin sensitivity at levels similar to wild-type BRCA1 protein (Bouwman 2013). However, the impact of this alteration on other aspects of BRCA1 protein function is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -
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Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:5Benign:1
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We detected an in-frame deletion in the BRCA1 gene (c.3328_3330delAAG) which results in the deletion of the amino acid lysine at position 1110. This mutation is considered as a variant of unknown significance. -
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Hereditary cancer-predisposing syndrome Benign:3
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
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not specified Benign:1
Variant summary: BRCA1 c.3328_3330delAAG (p.Lys1110del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00039 in 250772 control chromosomes, predominantly at a frequency of 0.0032 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001). c.3328_3330delAAG has been reported in the literature in individuals affected with breast and/or ovarian cancer without strong evidence for causality (e.g. Judkins_2005, Ahman_2012, Gleicher_2014, Mehta_2018, de Oliveira_2022, Hovland_2022), and was additionally found in an unaffected individual in the literature (Mannan_2016). Experimental evidence including an HDR assay evaluating impact on protein function showed no damaging effect of this variant (Bouwman_2013, Bouwman_2020). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 23867111, 19370767, 22486713, 25036526, 26911350, 28263838, 29785135, 32546644, 30555256, 35534704, 34981296). ClinVar contains an entry for this variant (Variation ID: 54840). Based on the evidence outlined above, the variant was classified as likely benign. -
Breast and/or ovarian cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at