rs80357272

chr17-43092083-G-Achr17-43092083-G-Cchr17-43092083-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_007294.4(BRCA1):c.3448C>T(p.Pro1150Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,976 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. P1150L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:7 B:9
• Conservation: PhyloP100: 6.27

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28494245).
• BP6: Variant 17-43092083-G-A is Benign according to our data. Variant chr17-43092083-G-A is described in ClinVar as [Benign]. Clinvar id is 54887.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092083-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3448C>T	p.Pro1150Ser	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3448C>T	p.Pro1150Ser	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251238 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461716 Hom.: 0 Cov.: 39 AF XY: 0.0000165 AC XY: 12 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000982

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:7 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Pro1150Ser variant was identified in 13 of 4830 proband chromosomes (frequency: 0.003) from Chinese and Korean individuals or families with breast cancer, and in 3 of 1892 control chromosomes (frequency: 0.002) from healthy individuals (Tang 1999, Li 2017 , Jang 2012, Suter 2004, Yang 2017, Yoon 2016). The variant was also identified in dbSNP (ID: rs80357272) as “With other allele”, in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: uncertain significance by Ambry Genetics, CHEO Genetics Diagnostic Laboratory, Laboratory of Molecular Diagnosis of Cancer, GeneDx, and BIC, and likely benign by Invitae and Laboratory Corporation of America), Clinvitae (5x), LOVD 3.0 (1x), BIC Database (5x), with unknown clinical importance, classification pending), and Zhejiang University Database (1x). The variant was identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic BRCA2 variant (c.3109C>T, p.Gln1037X); in addition, the variant was identified in UMD-LSDB 2x as 3-UV, co-occurring with a pathogenic BRCA1 variant (c.3181delA, p.Ile1061X), increasing the likelihood that the variant does not have clinical significance. The variant was not identified in Cosmic, MutDB, and ARUP Laboratories. The variant was identified in control databases in 18 of 276992 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 18 of 18866 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Pro1150 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance. -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00119 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13). -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2018	This alteration is classified as likely 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 30, 2015	- -

Breast neoplasm Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	Jun 10, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2022	Variant summary: BRCA1 c.3448C>T (p.Pro1150Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251790 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3448C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for pathogenicity (example, Haffty_2009, Haiman_2013, Liang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the UMD database (BRCA1 c.3181delA, p.Ile1061X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Lu_2015). The most pronounced variant effect results in approximately 89% of normal homology directed repair (HDR) activity suggestive of a non-significant impact on protein function. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign to include the expert panel. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2017	This variant is denoted BRCA1 c.3448C>T at the cDNA level, p.Pro1150Ser (P1150S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant has been previously published as BRCA1 3567C>T. This variant was observed in individuals with breast cancer, but was also seen in controls (Katagiri 1996, Tang 1999, Belogianni 2004, Jang 2012, Yoon 2016, Zhong 2016, Li 2017, Ryu 2017). A homologous-directed repair assay demonstrated that this variant results in homologous recombination activity similar to the wildtype protein (Lu 2015). BRCA1 Pro1150Ser was observed at an allele frequency of 0.095% (18/18866) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1150Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1150Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 11, 2023	- -

Ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Familial cancer of breast Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.9	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.99	D;.;.;D
Vest4		0.64
MVP		0.99
MPC		0.45
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.36

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: rs80357272; hg19: chr17-41244100; COSMIC: COSV100525526; COSMIC: COSV100525526;