About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.2531G>C, p.(Ser844Thr)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA1 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_007294.4:c.2531G>C is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls.
Benign criteria applied · 1
BP1Strong
BP1 · strong
c.2531G>C (p.Ser844Thr) is a missense substitution located at residue 844, which is outside all ENIGMA-defined clinically important functional domains for BRCA1 (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1). This meets ENIGMA BP1_Strong.
Recorded classification: Likely benign
ENIGMA BRCA1/BRCA2 v1.2 Table 3 point system for conflicting evidence. Only two criteria met: PM2_Supporting (+1 pathogenic point) and BP1_Strong (-4 benign points). Total = -3, which falls in the Likely Benign range (-6 to -2).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_007294.4:c.2531G>C (p.Ser844Thr) is a missense variant in BRCA1 exon 10, absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
The variant is located at residue 844, outside ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no splicing impact (max delta = 0.00), meeting BP1_Strong.
No functional assay data are available for this variant in ENIGMA-calibrated studies (PS3/BS3 not met). The variant was searched in the ENIGMA Table 9 curated functional assay results, ST4 full functional dataset, ST5 mammalian functional studies, and Parsons et al. 2019 datasets and was not found in any.
No clinical-history likelihood ratio is available from Li et al. 2020 (PMID:31853058) for this variant; c.2531G>C was not present in the BRCA1 clinical_history_LR table (PP4/BP5 not met).
Under the ENIGMA point system for conflicting evidence (Table 3), PM2_Supporting (+1) and BP1_Strong (-4) sum to -3, which falls in the Likely Benign range (-6 to -2). The variant is classified as Likely Benign.
No criteria match.
Met · 2
PM2 SupportingNM_007294.4:c.2531G>C is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Still missing
- Read depth at the variant position has not been independently verified
- ENIGMA requires average read depth ≥25 in the region.
Sources
BP1 Strongc.2531G>C (p.Ser844Thr) is a missense substitution located at residue 844, which is outside all ENIGMA-defined clinically important functional domains for BRCA1 (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1). This meets ENIGMA BP1_Strong. Details ▾Hide ▴
Evidence considered
- Variant is at residue 844
- outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains.
- SpliceAI max delta score = 0.00.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No previously classified pathogenic or likely pathogenic missense variant at BRCA1 codon 844 (p.Ser844) was identified in the ENIGMA reference variant set (ST7), curated functional assay table (Table 9), or the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001). Without a pathogenic comparator at the same residue, PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Extensive search of ENIGMA v1.2 tables for any pathogenic missense at BRCA1 codon 844 yielded no candidates. SpliceAI max delta = 0.00 confirms no predicted splicing effect.
Still missing
- No variant-specific data from literature could be identified for a pathogenic comparator at codon 844.
Sources
vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001cspec ↗
PS3 c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results. It was also absent from the full ST4 functional assay dataset (4,304 rows), ST5 BRCA1 mammalian functional studies, and the Parsons et al. 2019 functional assay cross-reference (SuppT4). No variant-specific functional evidence was identified in any ENIGMA-calibrated study. Details ▾Hide ▴
Evidence considered
- Exhaustive search of ENIGMA Table 9 (4
- 735 rows)
- ST4 (4
- 305 rows)
- ST5 (13 rows)
- and Parsons SuppT4 (89 rows) found no entry for c.2531G>C or p.Ser844Thr.
Still missing
- No functional assay data exist for this variant in any ENIGMA-calibrated study.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001cspec ↗
PS4 No case-control data demonstrating significantly increased prevalence in affected individuals versus controls (p≤0.05, OR≥4) are available for this variant. The variant is absent from gnomAD but there are no proband counts or case-control comparisons to satisfy the ENIGMA PS4 threshold. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- but absence alone does not meet PS4 case-control requirements.
Still missing
- No case-control study or proband count data available.
Sources
PP1 No co-segregation data are available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with an LR ≥ 2.08 (Supporting), ≥ 4.3 (Moderate), or ≥ 18.7 (Strong). Details ▾Hide ▴
Evidence considered
- No segregation or pedigree data available for c.2531G>C.
Still missing
- No family co-segregation data available.
Sources
PP3 ENIGMA PP3 requires either (a) BayesDel no-AF ≥ 0.28 for missense variants inside a clinically important functional domain, or (b) SpliceAI ≥ 0.2 for any missense/silent/intronic variant. p.Ser844Thr is outside all ENIGMA-defined functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI max delta = 0.00. BayesDel no-AF = -0.204893 does not meet the ≥ 0.28 threshold. Neither pathway to PP3 is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00.
- BayesDel no-AF score = -0.204893 (threshold for PP3 is ≥ 0.28).
- REVEL score = 0.564.
- Variant is at residue 844
- outside ENIGMA functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857).
Sources
PP4 ENIGMA PP4 is based on the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio model. c.2531G>C was searched in the BRCA1 clinical_history_LR table (1,329 rows) and was not found. The only nearby BRCA1 variant in the table was c.2633C>T, which is a different variant. No clinical history LR is available for c.2531G>C. Details ▾Hide ▴
Evidence considered
- c.2531G>C not present in Li et al. 2020 BRCA1 clinical-history LR table.
Still missing
- No personal or family history data available for individuals carrying c.2531G>C.
Sources
BA1 ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% (FAF > 0.001) in gnomAD v2.1 and/or v3.1 non-cancer, non-founder populations. The variant is absent from gnomAD in all datasets (v2.1, v4.1, Canada). Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada v1.0.
Sources
BS1 ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002% in gnomAD. The variant is absent from gnomAD in all datasets. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada v1.0.
Sources
BS2 ENIGMA BS2 requires observation of the variant in the absence of Fanconi Anemia phenotype features, scored via the points system in Specifications Table 8. No proband observation data are available for c.2531G>C. Details ▾Hide ▴
Evidence considered
- No individual-level observation data available.
Still missing
- No proband or population observation data for BS2 scoring.
Sources
BS3 c.2531G>C (p.Ser844Thr) is not listed in the ENIGMA Table 9 curated functional assay results for benign functional evidence. It was also absent from ST4, ST5, and Parsons et al. 2019 functional datasets. No variant-specific evidence of normal protein function is available. Details ▾Hide ▴
Evidence considered
- No entry for c.2531G>C in ENIGMA Table 9
- ST4
- ST5
- or Parsons SuppT4.
Still missing
- No functional studies demonstrating normal protein function for this variant.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001cspec ↗
BS4 No segregation data demonstrating lack of segregation with disease are available for c.2531G>C. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No co-segregation or lack-of-segregation data.
Sources
BP5 ENIGMA BP5 is based on the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio model for benign direction. c.2531G>C was not found in the BRCA1 clinical_history_LR table (1,329 rows). No LR is available to support BP5. Details ▾Hide ▴
Evidence considered
- c.2531G>C not present in Li et al. 2020 BRCA1 clinical-history LR table.
Still missing
- No clinical history data available for BP5 scoring.
Sources
PS5 PS5 requires both PS1 and PM5 to be met. Neither PS1 (no pathogenic comparator at codon 844) nor PM5 (missense, not a PTC variant under ENIGMA PM5_PTC rules) is met. Details ▾Hide ▴
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.2531G>C is a missense substitution (p.Ser844Thr), not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion). PVS1 applies only to null variants under the ENIGMA BRCA1/2 specification v1.2. Details ▾Hide ▴
Evidence considered
- ENIGMA PVS1 decision table (Table 4) is limited to null variants
- c.2531G>C is a missense and falls outside PVS1 scope.
Sources
PS2 VCEPENIGMA BRCA1/2 specification v1.2 marks PS2 as Not Applicable. Details ▾Hide ▴
PM1 VCEPENIGMA BRCA1/2 specification v1.2 marks PM1 as Not Applicable; captured by other domain analysis criteria within the specification. Details ▾Hide ▴
PM3 N/APM3 applies to recessive disorders where a pathogenic variant is detected in trans with another pathogenic variant. BRCA1-associated disease is autosomal dominant; PM3 is trivially not applicable in this context. Details ▾Hide ▴
Evidence considered
- Not applicable for autosomal dominant BRCA1-related hereditary breast and ovarian cancer.
PM4 VCEPPM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. NM_007294.4:c.2531G>C is a missense substitution and does not alter protein length. Details ▾Hide ▴
Evidence considered
- Trivially not applicable for a missense substitution variant.
PM5 N/AENIGMA PM5 is repurposed for PTC (protein termination codon) variants where a different proven pathogenic PTC variant has been observed in the same exon. c.2531G>C is a missense substitution (p.Ser844Thr), not a PTC. The classic same-residue missense PM5 is not applied under the ENIGMA BRCA1 framework. Details ▾Hide ▴
Evidence considered
- PM5_PTC applies only to protein termination codon variants per the ENIGMA specification.
Sources
pm5_candidatescspec ↗
PM6 VCEPENIGMA BRCA1/2 specification v1.2 marks PM6 as Not Applicable. Details ▾Hide ▴
PP2 VCEPENIGMA BRCA1/2 specification v1.2 marks PP2 as Not Applicable. Details ▾Hide ▴
PP5 VCEPENIGMA BRCA1/2 specification v1.2 marks PP5 as Not Applicable; reputable source reports are not used as independent evidence under this framework. Details ▾Hide ▴
BP2 VCEPENIGMA BRCA1/2 specification v1.2 marks BP2 as Not Applicable. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame deletions/insertions in a repetitive region without a known function. Not applicable to this missense substitution variant. Details ▾Hide ▴
Evidence considered
- Trivially not applicable for a substitution variant.
BP4 N/AENIGMA BP4_Supporting applies only to missense variants inside a (potentially) clinically important functional domain with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. p.Ser844Thr is outside all ENIGMA functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The precondition of domain localization is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = -0.204893
- SpliceAI = 0.00
- but variant is outside ENIGMA functional domains.
Sources
BP6 VCEPENIGMA BRCA1/2 specification v1.2 marks BP6 as Not Applicable. Details ▾Hide ▴
BP7 N/AENIGMA BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile. ENIGMA BP7_Supporting applies to silent variants inside a functional domain or intronic variants outside conserved splice positions. c.2531G>C is a missense variant with no mRNA splicing data available. Details ▾Hide ▴
Evidence considered
- Missense variant
- no mRNA transcript studies available for this variant.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.2531G>C
- Protein (HGVS p.)
- NP_009225.1:p.(Ser844Thr)
- GRCh38
- chr17:43093000 C>G
- GRCh37
- chr17:41245017 C>G
- ClinVar
- 867687, 844302, 233288
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.564
- BayesDel
- -0.205
How the predictions were used
PP3 ENIGMA PP3 requires either (a) BayesDel no-AF ≥ 0.28 for missense variants inside a clinically important functional domain, or (b) SpliceAI ≥ 0.2 for any missense/silent/intronic variant. p.Ser844Thr is outside all ENIGMA-defined functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI max delta = 0.00. BayesDel no-AF = -0.204893 does not meet the ≥ 0.28 threshold. Neither pathway to PP3 is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00.
- BayesDel no-AF score = -0.204893 (threshold for PP3 is ≥ 0.28).
- REVEL score = 0.564.
- Variant is at residue 844
- outside ENIGMA functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857).
Sources
BP4 N/AENIGMA BP4_Supporting applies only to missense variants inside a (potentially) clinically important functional domain with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. p.Ser844Thr is outside all ENIGMA functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The precondition of domain localization is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = -0.204893
- SpliceAI = 0.00
- but variant is outside ENIGMA functional domains.
Sources
BP7 N/AENIGMA BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile. ENIGMA BP7_Supporting applies to silent variants inside a functional domain or intronic variants outside conserved splice positions. c.2531G>C is a missense variant with no mRNA splicing data available. Details ▾Hide ▴
Evidence considered
- Missense variant
- no mRNA transcript studies available for this variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.564. BayesDel score = -0.204893.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004NSGC practice guideline describing cancer genetic risk assessment and counseling. Addresses hereditary breast and ovarian cancer at the gene level. NM_007294.4:c.2531G>C was not identified in this publication.Does not name this variant
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society guidelines for breast MRI screening as an adjunct to mammography. Discusses BRCA1/2 mutations in the context of high-risk screening eligibility. NM_007294.4:c.2531G>C was not identified in this publication.Does not name this variant
-
PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007NSGC recommendations for risk assessment and genetic counseling for hereditary breast and ovarian cancer. Discusses BRCA1/2 mutations at the gene level. NM_007294.4:c.2531G>C was not identified in this publication.Does not name this variant
-
PMID 19305347 ↗ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.2009ACOG Practice Bulletin No. 103 on hereditary breast and ovarian cancer syndrome. Provides clinical management guidelines for BRCA1/2 mutation carriers at the gene level. NM_007294.4:c.2531G>C was not identified in this publication.Does not name this variant
-
PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG policy statement on updated recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. Lists BRCA1 as a medically actionable gene. NM_007294.4:c.2531G>C was not identified in this publication.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_007294.4%3Ac.2531G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41245017-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43093000-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43093000-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.2531…
- OncoKB ↗www.oncokb.org/gene/BRCA1/S844T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.2531G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.564. BayesDel score = -0.204893.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.