rs56039126
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.1865C>T(p.Ala622Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A622G) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.1865C>T | p.Ala622Val | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.1865C>T | p.Ala622Val | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 251102Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135744
GnomAD4 exome AF: 0.0000828 AC: 121AN: 1461768Hom.: 0 Cov.: 34 AF XY: 0.0000839 AC XY: 61AN XY: 727172
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74316
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:4
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
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 = 0.0000212 - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
not specified Uncertain:1Benign:4
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 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: Multple papers describe as VUS; ClinVar: 2 B/LB, 3 VUS - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2019 | Variant summary: BRCA1 c.1865C>T (p.Ala622Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276900 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.1865C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, however, with limited information (ie, lack of co-occurrence and/or cosegregation data)(Tikhomirova_2007, Wagner_1998, Moghadasi_2013, Anczukow_2008, Borg_2010, Judkins_2005, Lee_2008, Palma_2008, Wong-Brown_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other likely pathogenic/pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908Argfs; BRCA2 c.658_659delGT, p.Val220Ilefs; BRCA2 c.6275_6276delTT, p.Leu2092Profs; BRIP1 c.440dupA, p.Tyr147X), providing supporting evidence for a benign role. Variant was functionally assessed to have no impact on splicing (Anczukow_2008). Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as likely benign/benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Ala622Val variant was identified in 5 of 26494 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 2 of 38,284 control chromosomes (frequency: 0.00005) from healthy individuals (Wong-Brown 2015, Moghadasi 2013, Momozawa 2018, Borg 2010, Lee 2008, Tikhomirova 2007). The variant was identified in dbSNP (rs56039126) as “with other allele”, ClinVar (classified as benign by Invitae, Color, Integrated Genetics, Ambry Genetics and ENIGMA, uncertain significance by Partners Healthcare, BIC and 2 other submitters and likely benign by GeneDx and University of Michigan), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 14x). The variant was identified in control databases in 15 of 267,978 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 117,956 chromosomes (freq: 0.0001), East Asian in 1 of 19,248 chromosomes (freq: 0.00005), Latino in 1 of 35,080 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish, Finnish, Other and South Asian populations. A clinical laboratory reported that the variant was identified with multiple co-occurring pathogenic variants (BRCA2 c.5722_5723delCT; p.Leu1908Argfs, BRCA2 c.658_659delGT; p.Val220Ilefs, BRCA2 c.6275_6276delTT; p.Leu2092Profs, BRIP1 c.440dupA; p.Tyr147*). In addition, the variant had no demonstrated effect on in vitro splicing (Anczukow 2008). The p.Ala622Val 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. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | BRCA1: BP1 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2020 | This variant is associated with the following publications: (PMID: 25637381, 18703817, 18284688, 21520273, 17990525, 23231788, 18273839, 23893897, 26898890, 9663595, 21990134, 17924331, 25682074, 20104584, 16267036, 15385441, 19370767, 33087888) - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2020 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 23, 2021 | - - |
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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 11, 2015 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at