rs80357127

Positions:

• chr17-43092805-T-A
• chr17-43092805-T-C
• chr17-43092805-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.2726A>T​(p.Asn909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,856 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N909Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:6
• Conservation: PhyloP100: -0.730

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1323534).
• BP6: Variant 17-43092805-T-A is Benign according to our data. Variant chr17-43092805-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37486.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Benign=2, Likely_benign=4}. Variant chr17-43092805-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2726A>T	p.Asn909Ile	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2726A>T	p.Asn909Ile	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 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: 0.000770

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: 0.0000798 AC: 20 AN: 250780 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

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: 0.0000185 AC: 27 AN: 1461660 Hom.: 0 Cov.: 47 AF XY: 0.0000220 AC XY: 16 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4 Benign:1

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 14, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 22, 1999	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 08, 2022	- -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2020	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 15, 2020	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2023	Variant summary: BRCA1 c.2726A>T (p.Asn909Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 279764 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to 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.2726A>T has been reported in the literature in individuals of Asian ancestry who were affected by breast or ovarian cancer, but was also found in healthy controls (e.g. Lai, 2017; Ahmadloo, 2017, Bhaskaran_2019, Kwong_2020, Momozawa_2018, Dorling_2021, Zhang_2022). In addition, a study classified this variant as likely benign based on a multifactorial probability model (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18627636, 22217648, 27257965, 26852015, 28364669, 28179634, 12602912, 29176636, 30287823, 30702160, 28222693, 30415210, 32068069, 35918668). Ten other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2016	- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2018

This variant is denoted BRCA1 c.2726A>T at the cDNA level, p.Asn909Ile (N909I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). Using alternate nomenclature, this variant has been previously published as BRCA1 2845A>T. This variant has been observed in individuals with a personal and/or family history of breast cancer, all of whom were of Asian ancestry, and was detected in 5/2091 breast cancer cases and 4/1462 controls in a study of multi-ethnic Asian individuals (Chen 2003, Thirthagiri 2008, Jang 2012, Cao 2016, Zhong 2016, Ahmadloo 2017, Arai 2017, Lai 2017, Park 2017). BRCA1 Asn909Ile was observed at an allele frequency of 0.12% (20/17,248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in DNA binding domain and in a region reported to interact with RAD51 (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Asn909Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Asn909Ile variant was identified in 21 of 23988 proband chromosomes (frequency: 0.0009) from individuals or families with breast or ovarian cancer and was present in 18 of 25598 control chromosomes (frequency: 0.0007) from healthy individuals (Arai 2018, Bhaskaran 2019, Cao 2016, Chen 2003, Jang 2012, Lai 2017, Momozawa 2018, Thirthagiri 2008). The variant was also identified in dbSNP (ID: rs80357127) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx and seven other submitters), LOVD 3.0 (6x), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 20 of 245542 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 20 of 17248 chromosomes (freq: 0.001), increasing the likelihood this could be a low frequency benign variant, while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asn909 residue is not 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) 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Uncertain	0.054	T;T;T;D
Polyphen		0.92	P;.;.;D
Vest4		0.38
MutPred		0.59		Gain of catalytic residue at N909 (P = 0.0053);Gain of catalytic residue at N909 (P = 0.0053);.;Gain of catalytic residue at N909 (P = 0.0053);
MVP		0.61
MPC		0.47
ClinPred		0.46	T
GERP RS		-4.7
Varity_R		0.18
gMVP		0.066

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: rs80357127; hg19: chr17-41244822;