BRCA1 c.1977del, p.Val660SerfsTer41
NM_007294.4:c.1977del
COSMIC ID: COSM6941416
Pathogenic
c.1977del (p.V660Sfs*41) is a BRCA1 frameshift variant leading to loss of function, absent in population databases and supported by functional studies. It meets PVS1, PS3, and PM2, consistent with a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.4:c.1977del
Protein Change
V660Sfs*41
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 660 in gene BRCA1
Alternate Identifiers
COSM6941416
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.1977del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 660 in gene BRCA1
Functional Summary
The BRCA1 V660Sfs*41 variant is a truncating mutation that likely results in loss of BRCA1 protein function. Functional evidence indicates that truncating mutations in BRCA1 can lead to aberrant protein folding, impaired DNA damage response, and elevated levels of aneuploidy in human breast cancer cell lines. Additionally, these mutations can cause aberrant protein localization, affecting interactions with binding partners. Mouse models with BRCA1 truncating mutations develop various cancers, supporting the damaging effect of such mutations.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows: c.1977del is a frameshift predicted to introduce a premature stop codon and cause loss of BRCA1 function. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where LOF is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change." The evidence for this variant shows: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied because the variant type does not meet PS1 requirements.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence has been reported. Therefore, this criterion is not applied because there is no de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional assays of truncating BRCA1 variants demonstrate loss of DNA repair function, aberrant folding, and tumorigenesis in models. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies; p≤0.05 and OR≥4)." The evidence for this variant shows: no published case-control data. Therefore, this criterion is not applied due to lack of case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: it is a frameshift variant, not a missense variant within a defined functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and gnomAD v3.1." The evidence for this variant shows: it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1-related Fanconi Anemia and co-occurring variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or trans configuration data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a frameshift causing LOF, which is covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Protein termination codon variant in an exon where a different proven pathogenic termination codon variant has been seen." The evidence for this variant shows: no specific documentation of another proven PTC variant in the same exon. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting In silico predictions support a deleterious effect for missense or in-frame variants or predicted splicing impact." The evidence for this variant shows: no in silico prediction for missense or splicing impact relevant to this frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Multifactorial likelihood clinical data in breast cancer families." The evidence for this variant shows: no multifactorial likelihood analysis data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Filter allele frequency >0.001 in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Filter allele frequency >0.0001 in gnomAD." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Applied in absence of features of recessive disease (Fanconi Anemia phenotype)." The evidence for this variant shows: no homozygous individuals reported but no FA phenotype data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro/in vivo functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong Silent, missense or in-frame variant outside a functional domain with no predicted splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in dominant disorder or in cis with a pathogenic variant in recessive disorder without phenotype." The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting No predicted impact via protein change or splicing for missense/in-frame or intronic variants." The evidence for this variant shows: not applicable to frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Co-occurrence with pathogenic variant in another gene without specific phenotype." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: none reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Silent variant with no predicted splicing impact or intronic variant outside splice sites." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.