17-43124032-A-G

Variant names:

• chr17-43124032-A-G
• rs80357438
• NM_007294.4:c.65T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.65T>C​(p.Leu22Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:2 O:1
• Conservation: PhyloP100: 4.17

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-43124032-A-G is Pathogenic according to our data. Variant chr17-43124032-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 55656.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124032-A-G is described in Lovd as [Pathogenic]. Variant chr17-43124032-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.65T>C	p.Leu22Ser	missense_variant	Exon 2 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.65T>C	p.Leu22Ser	missense_variant	Exon 2 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5 Uncertain:2 Other:1

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.99 -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Dec 14, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with serine at codon 22 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in loss of homology-directed recombination activity of BRCA1 protein (PMID: 25823446, 30219179, 30696104) and disrupts BARD1 binding activity (PMID: 30696104). This variant has been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 9609997, 19543972, 27741520, 29907814, 32380732, 32438681) and pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 22, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with serine at codon 22 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant has been reported to be functionally abnormal in homology-directed DNA repair assays (PMID: 25823446, 30219179, 30696104), a BARD1 binding assay (PMID: 30696104), and a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 9609997, 19543972, 27741520, 29907814, 32380732, 32438681) and pancreatic cancer (PMID: 29506128). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 21.151 from log(LR)=1.325323224 for 3 carriers (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 16, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L22S variant (also known as c.65T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 65. The leucine at codon 22 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in Japanese, Ashkenazi Jewish, Brazilian, German, Norwegian, and Italian HBOC families (Katagiri T et al. J. Hum. Genet. 1998;43:42-8; Sweet K et al. Breast Cancer Res. Treat. 2010 Feb;119:737–43; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Palmero EI et al. Sci Rep, 2018 Jun;8:9188). This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as 184T>C in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 17, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Pathogenic:2

Dec 16, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported as being pathogenic in the published literature (PMID: 19543972 (2010), 21990134 (2012), and 21990165 (2012)). Internal analysis of published breast and ovarian cancer cases revealed an enrichment of the variant in cases compared to general population controls (PMID: 9609997 (1998), 25452441 (2015), and 29907814 (2018)). Comprehensive functional studies indicated that this variant is damaging to E3 ubiquitin-ligase activity of the BRCA1 protein (PMID: 25823446 (2015)), while another study utilizing a yeast model yielded inconclusive predictions on the effect of the variant on BRCA1 protein function (PMID: 27272900 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Feb 26, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (PMID: 9609997, 19543972, 25452441, 27741520, 27225819, 28888541, 29506128, 32438681, 34981296, 39176249); Published functional studies suggest a damaging effect based on E3 ubiquitin ligase ability, HDR activity, colony size, and liquid medium function, while other functional assays demonstrated BARD1 binding, spot formation, and yeast localization comparable to wild-type (PMID: 25823446, 27272900, 30209399, 30219179); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 19543972, 21990134, 21990165); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 184T>C; This variant is associated with the following publications: (PMID: 27225819, 25452441, 18951461, 24489791, 19543972, 25525159, 21990165, 24281179, 22753008, 9609997, 27272900, 25823446, 28408614, 27741520, 29339979, 29506128, 29907814, 29446198, 30219179, 30209399, 33087888, Paquette[article]2021, 35659930, 34572941, 34906479, 35534113, 34981296, 28888541, 32438681, 21990134, 24389207, 20104584, 38069422, 30696104, Mateu-Regue2024[FunctionalStudy], 38386807, 39176249) -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 22 of the BRCA1 protein (p.Leu22Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9609997, 19543972, 25452441, 28888541, 30339520, 32438681, 34981296). ClinVar contains an entry for this variant (Variation ID: 55656). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21990134, 25823446, 30209399, 30696104). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.65T>C (p.Leu22Ser) variant involves the alteration of a conserved nucleotide located in the Zinc finger, RING/FYVE/PHD-type (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 245708 control chromosomes, and has been reported in numerous affected individuals in the literature. Additionally, functional evidence has shown the variant to result in reduced HDR levels (Starita_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. -

Infant-type hemispheric glioma Pathogenic:1

Nov 05, 2021

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.7	L;L;L;L;L;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.2	N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;T;D;D;T;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		0.98, 0.99, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.92
MutPred		0.92		Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);Loss of stability (P = 0.0745);
MVP		0.97
MPC		0.53
ClinPred		0.95	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357438; hg19: chr17-41276049;