rs80357048
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.4910C>T(p.Pro1637Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1637A) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4910C>T | p.Pro1637Leu | missense_variant | 15/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4910C>T | p.Pro1637Leu | missense_variant | 15/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251356Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135868
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727244
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:4Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000627 - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 01, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2016 | Variant Summary: This variant involves alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome (SNP&GO not captured here due to low reliability index). This variant was found in 3/121924 control chromosomes at a frequency of 0.0000246, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0010005). Variant has been reported in multiple affected individuals without evidence for causality. In particular, this variant is found to commonly co-occur with the BRCA1 pathogenic variant c.2457delC (internal data, BIC database, Humphrey_1997, and Tavtigian_2006), suggesting this variant of interest is in linkage disequilibrium and has been suggested to be a rare polymorphism per Humphrey_1997. In addition, multiple publications (Easton_2007, Lindor_2012 and Humphrey_1997), clinical labs, and databases (ARUP, ClinVar, Invitae, SCRP) classify the variant as benign/likely benign. Functional studies suggest that the variant acts comparably to wild-type (Humphrey_1997 and Coyne_2004). Considering all, variant is classified as Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2020 | This variant is associated with the following publications: (PMID: 25782689, 22753008, 15004537, 18284688, 16014699, 17924331, 7939630, 9159158, 26689913, 21990134, 24448499, 11183185, 28398198, 28781887, 30209399, 30765603, 33087888) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified as benign by expert panel (8/10/15) - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Pro1637Leu variant was identified in 1 of 858 proband chromosomes (frequency: 0.001) from individuals or families with ovarian cancer (Kanchi 2014). The variant was also identified in dbSNP (ID: rs80357048) as "With Uncertain significance, other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics and four other submitters; as likely benign by two submitters and as uncertain significance by two submitters), MutDB , LOVD 3.0 (8x), UMD-LSDB (6x as unclassified variant), BIC Database (67x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in the COGR, Cosmic, or Zhejiang University, databases. The variant was identified in control databases in 5 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111576 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro1637 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The multifactorial probability based model determined the variant has posterior probability of being deleterious 6.27×10-5 and predicted to be neutral with odds of neutrality = 493 (Lindor 2012, Easton 2007). In addition, in several publications the variant observed with one or more known truncating mutations (Kanchi 2014, Tavtigian 2006), increasing the likelihood that the p.Pro1637Leu variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
BRCA1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 18, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at